LONG PHOTOPERIOD HAS ANTIDEPRESSANT EFFECT IN RATS
by Shuntaro Tadano
Muskingum College 2009
Approved By
________________________ Advisor Program in Neuroscience
Antidepressant effects of long photoperiod 2 Table of Contents Table of Contents............................................................................................................................ 2 Abstract ........................................................................................................................................... 3 Introduction..................................................................................................................................... 4 Symptoms ................................................................................................................................... 4 Treatment of SAD....................................................................................................................... 5 Bright Light Therapy............................................................................................................... 5 Sleep Deprivation.................................................................................................................... 7 Anti Depressant Drugs............................................................................................................ 7 Mechanisms ................................................................................................................................ 8 Neuropsychology..................................................................................................................... 8 Neurochemistry ..................................................................................................................... 12 Neuroanatomy....................................................................................................................... 15 Animal Model ........................................................................................................................... 20 Materials and Methods.................................................................................................................. 22 Subjects ..................................................................................................................................... 22 Apparatus .................................................................................................................................. 22 Procedure .................................................................................................................................. 22 Results........................................................................................................................................... 23 Discussion ..................................................................................................................................... 23 References..................................................................................................................................... 27 Table 1 .......................................................................................................................................... 38 Table 2 .......................................................................................................................................... 39 Figure Caption .............................................................................................................................. 40
Antidepressant effects of long photoperiod 3 Abstract Recurrence of depressive episode in seasonal affective disorder (SAD) shows ultradian rhythmicity. Development of the symptoms is found in autumn or winter and diminishment is found in spring or summer. Photoperiod has been thought to be a primary driving force for such seasonality. In the present study, effect of photoperiod on the behavior of rats was assessed by forced swim test (FST), a widely used tool to assess depression-like activity in rats. Each rat was placed into a rectangular plastic container filled with water at room temperature, and time spent immobile was recorded. Results showed a significant decrease in time spent immobile by rats housed under long photoperiod (20L/4D). This suggests that long photoperiod has antidepressant effect and may explain diminishment of the episodes in SAD patients under long photoperiodic environment.
Antidepressant effects of long photoperiod 4 Long Photoperiod Has Antidepressant Effect in Rats Introduction Seasonal Affective Disorder (SAD) was first described by Rosenthal in 1984. It was originally defined as a syndrome which developed depression in autumn or winter and remitted in spring or summer, occurring for at least two successive years. Now, SAD is defined as a specifier of either bipolar or recurrent major depressive disorder (APA, 1994). The interesting facts of SAD are that exposure to bright light is as much effective as antidepressant, and in northern hemisphere, traveling south during winter improves depressive episode but the episode returns within days of returning north (Jacobsen, Wehr, Sack, James, and Rosenthal, 1984). On the one hand, Teng, Akerman, Cordas, Kasper, and Vieira (1995) found that a patient in a tropical country showed seasonality when they had depressive episode, and light therapy was effective. However, this patient did not match symptoms of SAD and was diagnosed as bipolar II according to DSM-III-R. Symptoms The symptoms of SAD are depressed mood, increased duration of sleep, increased appetite, weight gain, and carbohydrate craving (Magrusson & Partonen, 2005). The last four symptoms are often called atypical depressive symptoms. In addition, patients may suffer from general symptoms of depression such as diminished pleasure, fatigue, or feeling of worthlessness. Sigmon et al. (2007) studied a difference in response time between patients of SAD, major depression (MD), and healthy controls. Their results showed that both SAD and MD patients showed attentional bias toward depressive stimuli. However, MD patients took longer time to respond to color name words while SAD patients did not. This study suggests that SAD
Antidepressant effects of long photoperiod 5 patients are sensitive to seasonal stimuli and it distinguishes seasonal and nonseasonal depression. Lam, Tam, Yatham, Shiah, and Zis (2001), on the other hand, claims that there are other types of “winter depression”. Some SAD patients show incomplete summer remission (ISR) while other patients do not meet criteria of major depression in winter (subsyndromal SAD or sub-SAD). Treatment of SAD Although its mechanisms are unclear, many studies reported effectiveness of exposure to bright light. Total sleep deprivation for a night shows short lasting effect on some depression although its mechanisms are not known. Antidepressants are suggested as effective. Bright Light Therapy Decreased time of sunlight exposure in winter is hypothesized to be a main factor of SAD and therefore additional exposure to the light is recommended as a choice of a treatment (Eastman, Young, Fogg, Liu, & Meaden, 1998). However, it remains unclear that how exposure to the light has a therapeutic effect, and if the light therapy has more effect than placebo. It has been known that circadian rhythms are shifted in SAD and depressed patients (Lewy, Sack, Miller, & Hoban, 1987). According to the phase-shift hypothesis, morning light causes phase-advance and therefore it has more antidepressant effect than evening light on the SAD patients. A study by Lewy et al. (1998) showed statistically significant effect of the morning light (2500 lx, 0600-0800h) over evening light (2500 lx, 1800-2000h). Tsai, Hsiao, and Wang studied antidepressant effect of infrared light (IR) on laboratory mice (2007). The mice were housed in natural light/dark cycle (daytime: 0630h-1730h). The average emissivity of the infrared light between 3-15 μ was 0.919 and its maximal radiation intensity was 33 joule/cm2. The experiment mice were exposed the infrared light for one hour
Antidepressant effects of long photoperiod 6 (1600h-1700h) for four weeks. The result showed significantly different immobility times in FST between the experimental mice and the controls after the exposure. Meesters, Beersma, Bouhuys, and van den Hoofdakker (1999) studied antidepressant effect of infrared light. The SAD patients participated and they were asked to be exposed to bright white visor light (2500 lx), infrared light (0.18 lx), or no light for 30 minutes a day between 0600h and 0900h. There was no statistical difference in age, gender, or season of participation between the participants. The results showed that 36% of the participants exposed to the bright light, 7% of participants exposed to the IR, and 78% of controls developed a depression. Analysis showed statistical difference between bright light and IR, bright light and control and IR and control. Cohen, Gross, Nordahl, Semple, Oren, and Rosenthal (1992) studied metabolic rate in the brain of SAD treated with the light therapy and not treated with the therapy. They found that relatively low activity around the globe, at superior medial frontal cortex, and high rates in basal ganglia in both SAD patients. Non-light-treated patients showed “higher metabolic rates in right parietal and medial orbitofrontal cortex and lower rates in the left parietal cortex.” Many studies on placebo effect of the light therapy were conducted. It is perceived that bright light is effective to some extent in general, and therefore, a setting of the placebo control is crucial for the study. As a placebo control, Eastman, Young, Fogg, Liu and Meaden (1998) used negative-ion generators. After three weeks of trial, bright light in the morning showed significant antidepressant effects over placebo. Lam et al. (2001) found that sub-SAD patients responded more than SAD and ISR respectively. In addition, bright light therapy (10,000 lx, 1 h/day, before 1000h) shows additional
Antidepressant effects of long photoperiod 7 effectiveness in non-seasonal depression patients who are treated with sertraline at the same time (Martiny, Lunde, Unden, Dam, & Bech, 2005). Sleep Deprivation Sleep deprivation shows 40 to 60 percent of improvement after one night but after recovery sleep, without medication, 50 to 80 percent of patients experienced relapse. The improvements may last for weeks (Giedke & Schwärzler, 2002). It is suggested that sleep deprivation affects on serotonergic systems showing short-lasting antidepressant effect. Neumeister et al. (1998) studied effects of tryptophan depletion after the sleep deprivation. Both patients and controls who had depressive symptoms with tryptophan depletion showed increased in their mood after the sleep deprivation. Increased plasma tryptophan level was seen in the sham testing participants while decreased level was seen in the tryptophan depleted patients. After the recovery sleep, many tryptophan depleted patients, but not controls, showed prevention of replacing depression. Anti Depressant Drugs For a treatment of the major depression, antidepressant drugs and/or psychotherapy are primary choices. The first recommended drug is selective serotonin reuptake inhibitors (SSRIs) (Danese & Pariante, 2008). The second choice of the drug is other type of SSRI or different class of drugs including noradrenergic and specific serotonergic antidepressants (NaSSA), norepinephrine reuptake inhibitors (NRI), tricyclic antidepressants (TCA), or monoamine oxidase inhibitors (MAOI). Other options such as serotonin-norepinephrine reuptake inhibitors (SNRI), electroconvulsive therapy (ECT) are available if necessary. Lithium (400 mg/day) is sometimes prescribed for mild bipolar affective disorder.
Antidepressant effects of long photoperiod 8 Mechanisms SAD is a mood disorder. Mood disorders are characterized by the fundamental disturbance of change in mood (depressive or manic), which is usually accompanied by a change in the overall level of activity (ICD-10, 2007). Subjective mood is a result of neuronal activities and, therefore, mechanisms of SAD can be explained by looking at activities of the brain. In this section, mood and environmental stresses, chemical dynamics of the brain, and fundamental neural structures are visited. Neuropsychology As a result of neural activities which process sensory inputs, mood can be affected by external environment. In order to understand those external stresses on moods and behaviors, effects of light and temperature are mainly focused. Mood and Emotion. Studies on seasonality of mood provide complex results, and thorough consideration of sample collections and types of measurement are essential. A study conducted in Australia over three years showed small effects of season among samples although a sub-group in the sample showed stronger seasonality (Murray, Allen, & Trinder, 2001). Mood is a subjective state and mood disorder is caused by dysfunction of the brain. Therefore, it is important to describe mood from neuronal perspective. Damasio (1999) stated that mood consisted of basic emotions and background emotions. The basic emotions include happiness, surprise, anger, disgust, sadness, and fear. The background emotions are such as tiredness, motivation, excitement, balanced, stability, and so on. Lane (2006) presented a cognitive developmental model of emotional awareness and a parallel hierarchical model of the neural substrate of emotional experience. These hierarchies
Antidepressant effects of long photoperiod 9 consist of five levels. Function of each level adds to and modifies a function or functions of the previous level but do not eliminate. Lower levels correspond to unconscious or implicit emotional processes while higher levels correspond to conscious or explicit emotional processes. According to Lane, domain-general (i.g. not specific to emotion) function of neural structures play a role to the conscious awareness of feelings. The primary level of neural structures for conscious emotional experience which address background feelings are orbitofrontal cortex, ventromedial prefrontal cortex, ventral and pregenual anterior cingulated cortex, insula, temporal pole, and parietal lobe. Patients with bipolar disorders showed dysfunction in prefrontal and subcortical neural networks including dorsal anterior cingulate cortex and medial orbitofrontal cortex (Green, Cahill, & Malhi, 2007). Abnormal metabolic rate of both prefrontal and parietal cortex regions were found in SAD by PET (Cohen, Gross, Nordahl, Semple, Oren, & Rosenthal, 1992). Stress and the Hypothalamic-Pituitary-Adrenal (HPA) axis. Hypothalamic-pituitaryadrenal (HPA) axis is a carefully coordinated system which produces cortisol. Paraventricular nucleus (PVN) releases corticotropin-releasing hormone which leads adrenocortico tropic hormone (ACTH) and this is followed by release of cortisol (Yi & Baram, 1994). Cortisol has a wide range of central and peripheral effects (Watson & Mackin, 2006). In depression, the HPA axis is highly activated and SCN shows lower level of vasopressin, which leads activation of CRH (Swaab, Bao, & Lucassen, 2005). Bhatnagar and Dallman (1999) studied effects of stress on metabolism and related neural activity. They found that stressed rats showed lower amplitude of core temperature rhythmus. However, lesions of the posterior division of the paraventricular nucleus of the thalamus led no change in the amplitude of temperature rhythmus under chronic stress.
Antidepressant effects of long photoperiod 10 Dalla et al. (2005) studied different response to stress between male rats and female rats. Results showed that female rats were more vulnerable to chronic mild stress than male although they showed better response to an additional-novel stressor that was FST. Circadian Rhythms. Circadian rhythm is “a biological rhythm that persists under constant conditions with a period length of a day” (Foster & Kreitzman, 2004). Photoperiod. Exposure to abnormal photoperiod leads behavioral changes in animals. Briaud, Zhang, and Sannajust (2004) studied effects of continuous light on Wistar rats. One of the findings is that the exposure for 17 weeks caused complete suppression of their blood pressure, heart rate, systolic blood pressure, and body temperature circadian rhythms. Diastolic blood pressure was high compared to controls (12L/12D) during the theoretical resting period (0800h-2000h). Molina-Hernandez and Tellez-Alcantara (2000) studied effects of long photoperiod (14L/10D). It showed that long photoperiod seemed to have antidepressant effects as well as Clomipramine and Desipramine did in both FST, and differential reinforcement performance under the differential reinforcement of low-rate 72 second schedule. Prendergast and Kay (2008) showed that rats exposed to short light periods (10L or 12L) for more than seven weeks had higher scores of behavioral despair, anxiety and sucrose anhedonia relative to 14L rats according to an open field test, FST, and sucrose preference test. In addition, the resting concentration of ACTH was lower in 10L and 12L rats compared to 14L rats. Another experiment was on the female rats. An open field test and elevated plus maze test were conducted and the results suggested that short photoperiod (8L) had an assisting effect, or long photoperiod (16L) had a weakening effect on anxious-corresponding behaviors (Benabid, Mesfioui, & Ouichou, 2008). Gonzalez and Aston-Jones (2008) studied effects of light deprivation on Sprague-Dawley male rats. The subjects were kept totally dark room for 6 weeks.
Antidepressant effects of long photoperiod 11 Results showed changes in noradrenergic locus coeruleus, serotonergic raphé nucleus, and dopaminergic ventral tegmental area. FST revealed that test subjects showed increase in immobile time. Light deprivation did not affect either body or adrenal weights but increased sensitization to stress. Other rodents show sensitivity to photoperiodic change. Einat, Kronfeld-Schor, and Eilam (2006) studied an effect of a short photoperiod (5L/19D) on a diurnal rodent, fat sand rat (Psammomys obesus). After three week of photoperiod change, FST was conducted and a group under short photoperiod showed significant depressive-like activity while no significant difference was found in open field studies. Mammals seem to use photoperiod for their cycle of reproduction, and pineal gland and the suprachiasmatic nucleus are involved in the seasonal breeding patterns (Elliott, 1976). However, a study on Syrian Hamsters (Mesocricetus auratus) by Heideman and Broson (1993) showed poor within-group synchrony during testicular regression in those which were exposed to photoperiod mimicked a change of 5º of latitude. The Syrian hamster is reported to have sensitivity to respond changes in photoperiod. For example, Prendergast and Nelson (2005) showed that shorter photoperiod (8L) increased amount of floating time. Therefore, it suggests that non-photoperiodic cues might be used for seasonal breeding in mammals in the deep tropics. Temperature. Temperature can be a stressor and affects biological and psychological functions. Sharma and Panwar (1987) studied cognitive ability under moderate cold temperature. After three-hour exposure to cooler environment (15ºC or colder) than comfortable temperature at 25ºC, participants showed definite impairments in simple mental functions.
Antidepressant effects of long photoperiod 12 Neurochemistry In the patients of mood disorder, abnormal electrical and chemical activities of the brain are found, and most of the treatments focus on changing its chemical activities. From now on, relationship between light and melatonin and neurotransmitters are explained. Melatonin. Phase advance in melatonin production is found in SAD patients. The SAD patients were received phototherapy (> 2,000 lx) between 0600h and 0800h, and 1800h and 2000h (Terman et al., 1987). After one week of the therapy, all the patients showed clinical and phase-advance remissions. Partonen, Vakkuri and Lonnqvist (1997) studied difference in concentration of melatonin in saliva between healthy participants and SAD patients. The result showed that different length of time to expose 3300 lx light for either five minutes or sixty minuets did not make any significant difference in melatonin concentration. In addition, they found no correlation between subjective sleepiness and melatonin concentration. Nathan, Burrows, and Norman (1999) studied sensitivity to dim light (200 lx, between 2400h and 0100h) among affective disorder patients. Blood samples were collected through catheter, and plasma melatonin was measured. While major depressive disorder patients showed no difference of sensitivity with controls, SAD and bipolar disorder patients showed supersensitive melatonin suppression to dim light. Wehr et al. (2001) studied seasonal changes in melatonin secretion in SAD patients and healthy participants. Blood samples were collected through intravenous every 30 minutes for 24 hours. As a result, SAD patients showed seasonal changes in plasma melatonin levels while healthy participants showed no seasonal changes. Melatonin was secreted longer in winter and
Antidepressant effects of long photoperiod 13 shorter in SAD patients and this is similar to the signal that mammals use to control their different behavior in season. Since melatonin is secreted in nocturnal animals during dark period, it is suggested that melatonin is a hormonal signal of darkness rather than inducing sleep by itself (Turek & Gillette, 2004). Neurotransmitters. Since light therapy has antidepressant effect, it can be suspected that neurotransmitters involve in the therapeutic mechanisms. It is suggested that depression is influenced by both gene and environment. Studies have suggested that depressed patients showed decreased responsiveness to change in serotonin due to abnormality of transporters. Neumeister et al. (2002) studied a relationship between tryptophan depletion (TD), genetic factor, and family history of depression focusing on serotonin transporter gene promoter polymorphism. The participants were healthy women and had either positive or negative family history of depression and they have serotonin transporter gene promoter polymorphism as a type of a deletion-insertion (5HT-transporter-linked polymorphic region (5HTTLPR)). The 5HTTLPR is a transcriptional control region located near several potential binding sites for transcription factors, including SP1, AP1, and AP2 (Heils et al., 1996). The result showed that short form of polymorphism and positive family history of depression were associated with increases of the Hamilton Depression Scale, namely increase risk of depression during TD. An important role of serotonin in circadian rhythm has been showed by Morin and Blanchard (1991). They depleted serotonin in brain of hamster by central 5,7dihydroxytryptamine (DHT) application. As a result, 90 % of cells were lost from dorsal raphé nucleus and density of the serotonergic terminal area in the SCN and intergeniculate leaflet
Antidepressant effects of long photoperiod 14 (IGL) decreased. The hamsters showed modified circadian locomotor rhythms compared to the controls. Untreated depressive patients show lowered monoamine levels. Studies on monoamine transporters and monoamine synthesis enzymes have not revealed the processes. Mayer et al. (2006) studied specific distribution volume of monoamine oxidase A (MAO-A) which metabolizes monoamines in major depressive disorder patients with positron emission tomography. The result showed 34 percent elevation in MAO-A density in depressed individuals. Although it is not clear that the increase are from a greater number of MAO-A attached mitochondrion or greater number of MAO-A per mitochondrion, an importance of MAO-A density in reducing monoamine during untreated major depression. Neumeister et al. (1998) studied possible involvement of catecholamine in light therapy in SAD patients. The SAD patients who had responded bright light therapy (10,000 lx) were examined. For catecholamine depletion, they were given tyrosine hydroxylase inhibitor αmethyl-paratyrosine (AMPT). As sham depletion, they were given Diphenhydramine hydrochloride which gave them similar drowsiness and fatigue to AMPT did. It has been studied involvements on serotonin in light therapy, and now the results showed that catecholamine depletion made the light therapy less effective and indicate involvements of catecholaminergic systems in the therapy. Hebert, Beattie, Tam, Yatham, and Lam (2004) found decreased sensitivity to blue-green light in retina of SAD patients. Since activities of rod are favored by melatonin while dopamine favors activities of cone and melatonin suppression is mediated by D2/D4 receptors, researchers hypothesized that irregular coordination between melatonin and dopamine underlies SAD development.
Antidepressant effects of long photoperiod 15 Partonen (1996) also suggested involvements of dopamine in SAD because dysfunction of thermal control in SAD patients seems due to abnormal dopamine availability. An observation of extracellular neurotransmitter activities in prefrontal cortex during the forced swim test by freely moving microdialysis showed that extracellular level of DA underlies immobility in FST and to an extent NE levels (Kobayashi, Hayashi, Shimamura, Kinoshita, & Murphy, 2008). In contrast, this study showed that 5-HT reuptake blockers are failed to change its behavior in FST. Neuroanatomy Neural structures which are in charge of circadian rhythm are mainly gathered in a small area called hypothalamus. It is not surprising that those structures play important roles in sleep/awake cycle with a help of environmental light. In this part, retinal ganglion cells and important hypothalamic nuclei are explained. Retinal Ganglion Cells, Melanopsin. Numbers of studies on retinal ganglion cells have been conducted (Leak & Moore, 1997; Berson, Dunn, & Takao, 2002). Among those studies, a finding of new photopigment called melanopsin which is neither rods nor cones was a sensation (Soni, Philp, & Foster, 1998; Hankins, Peirson, & Foster, 2007). Melanopsin plays an important role in circadian rhythm, and unlike the other photopigments, it requires light stimuli of high intensity and long duration (Hankins, Peirson, & Foster, 2007). Other study supports existence of the third photoreceptor. Freedman et al. (1999) showed remaining phase-shift response to light in mice which lacked both cones and rods while mice which lacked the eyes did not show this behavior. Sprachiasmatic Nucleus (SCN). SCN is a center for the circadian rhythms. Several studies have suggested that mutation of circadian genes is associated with bipolar affective
Antidepressant effects of long photoperiod 16 disorder patients (Shi et al., 2008). Roybal et al. (2007) created mutant mice that produced dominant-negative CLOCK protein that could not transcript. Behavioral observation of these mice showed mania-like activities such as less helpless movement measured by FST. Abrahamson and More (2001) studied neural difference between core and shell subdivision of the SCN in mice. The distinction between the two subunits is based on chemostructure and can be found in other mammals. Only the core SCN receives photic information from the retina and intergeniculate leaflet, and from raphé nucleus. The shell SCN, on the other hand, does not receive photic input but receives massive input from the core and other brain regions. Table 1 shows difference in neurons between the subdivisions. SCN innervate several nuclei. Arginine vasopressin (AVP) is a neuropeptide and AVP neurons projecting from SCN inhibit corticotropin-releasing-hormone (CRH) in the paraventricular nucleus (PVN) (Kalasbeek, Buijs, van Heerrikhuize, Arts & van der Woude, 1992). It has been found greater number of CRH expressing neurons and greater number of CRH neurons co-expressing AVP in the PVN of major depressed patients (Raadsheer, Hoogendijk, Stam, Tilders, and Swaab, 1994). Zhou et al. (2001) studied amounts of AVP-immunoreactive (AVP-IR) neurons and AVP-messenger RNA (mRNA) in the SCN of brains of subjects who suffered from major depression and bipolar disorder, and that of controls. They found increased number of AVR-IR neurons in the SCN of the depressed patients and decreased number of AVP-mRNA. It suggests that impairment of circadian rhythms and sleep disorder in depression patients seems to be a result of dysfunction of the AVP production and transportation in the SCN (Swaab, Bao, & Lucassen, 2005).
Antidepressant effects of long photoperiod 17 Saint-Mleux et al. (2007) studied an influence of SCN on the ventrolateral preoptic nucleus (VLPO) in vitro. They found unexpectedly that train stimulations of the SCN evoked a long-lasting inhibition (LLI) and the LLI was, too, evoked in the VLPO neurons by pressure injection of NMDA in the SCN. In addition, the LLI was suppressed by application of yohimbine, Deurveilher and Semba (2005) studied innervations between SCN and medial preoptic area (MPA), subparaventricular zone (SPVZ), and dorsomedial hypothalamic nucleus (DMH), and then they farther studied projections from these three nuclei. They found moderate and dense anterograde labeling in the orexin cell field and the Tuberomammillary nucleus. Medial Preoptic Nucleus (MPN). Uschakov, Gong, McGinty and Szymusiak (2007) studied an involvement of MPN in the sleep and arousal activity. Anterograde and retrograde neuroanatomical tracers were used to observe neural connectivity. Projection to the locus coeruleus was found and labeled axons were found within the lateral division of the dorsal raphé nucleus and ventrolateral periaqueductal gray were observed. Lu, Jhou, and Saper (2006) found that dopaminergic neurons which are active during wakefulness and which are non-active during sleep in the ventral periaqueductal gray by detecting c-Fos protein expression. Their anterograde and retrograde tracing methods with tyrosine hydroxylase (TH) and Fos immunostaining revealed afferent and efferent projections of these wake-active dopaminergic cells showing in the Table 2. Gvilla, Xu, McGinty, and Szymusiak (2006) studied activation of c-Fos protein immunoreactivity (IR) in GABAergic neurons in the MPN and the vetrolateral preoptic area after spontaneous sleep in the light, spontaneous sleep in the dark, sleep deprivation (SLD) in the light and recovery sleep after SLD in the light. After the SLD in the light, the number of GABAergic neurons expressing c-Fos-IR was higher in the MPN compared with the spontaneous sleep and
Antidepressant effects of long photoperiod 18 the recovery sleep in the light. On the other hand, GABAergic neurons expressing Fos in the ventrolateral preoptic area were prevalent after spontaneous sleep and recovery sleep. Paraventricular Nucleus (PVN). Activation of HPA axis during stress involves increased activity of the posterior division of the PVN (Bhatnagar, S. & Dallman, M. F., 1999). It is suggested that hyperactivity of oxytocin neurons in the PVN relates to the eating disorder in depression (Swaab, Bao, & Lucassen, 2005). Kirouac, Parsons, and Li (2005) found orexin neuron projections from lateral and perifornical regions of the hypothalamus to the PVN although its influence is unknown. Dorsomedial Hypothalamic Nucleus (DMH). DMH receives inputs from SCN and lesion of DMH decreases sleep-awake circadian rhythm (Saper, Lu, Chou, & Gooley, (2005); AstonJones, Chen, Zhu, & Oshinsky, 2001). Ventrolateral Preoptic Nucleus (VLPO). VLPO has been known its inhibitory function. VLPO neurons are GABAergic and galaninergic, which innervate the monoaminergic cell groups related to arousal system. To study retinal influence on the VLPO, Lu, Shiromani, and Saper used cholera toxin B and Fos (1999). They found that the terminals of retinal projection formed appositions with the cell bodies and dendrites of the galaminergic VLPO neurons. In addition, injection of Fluorogold into the VLPO revealed projections to ganglion cells in the retina, which suggested unique luminance-sensitive ganglion cells that regulate biological clock. Sherin, Elmquist, Torrealba, and Saper (1998) showed that the VLPO projects GABAergic and galaninergic neurons to the cell bodies and proximal dendrites of the tuberomammillary nucleus. Chou et al. (2002) studied neural projections involving the ventrolateral preoptic nucleus. Retrograde tracer cholera toxin B subunit (CTB), or Anterograde tracer biotinylated
Antidepressant effects of long photoperiod 19 dextranamine (BD), Phaseolous vulgaris leucoagglutinin (PHAL), or wheat germ agglutininhorseradish peroxidase (WGA-HRP) were injected to the VLPO of rats. After the appropriate labeling, the brains were observed. The results showed that VLPO receives inputs from monoaminergic systems, specific hypothalamic, limbic, and autonomic regions. Little or no dopaminergic or cholinergic inputs were found. It suggests innervations of sleep-active VLPO neurons and wake-active monoaminergic neurons. Tuberomammillary Nucleus (TMN). TMN is a histamine containing neurons consisting of five subgroups located in the posterior hypothalamus (Inagaki et al., 1990). Later Ko, Estabrooke, McCarthy and Scammell (2003) studied the activation of the histaminergic neurons of three subnuclei of the TMN (dorsomedial, ventrolateral, and caudal TMN). They found that the neurons were wake active regardless of the time of day. Hyun, Beob, amd Barry (2005) found neural projections from the TMN to the dorsal raphé and the locus coeruleus. Some TMN neurons have axon collaterals. Lesions of TMN especially its subgroups, E1 (caudal ventral tuberomammillary nucleus) and E2 (rostral ventral tuberomammillary nucleus), lead increase of food intake (Mahia & Puerto, 2006). Orexin Neurons. Orexin (orexin A and B)/hypocretin are newly found neuropeptides. Peyron et al. (1998) studied orexin neurons in the rat brain. The prominent projection was in the locus coeruleus. Labeled neurons were also found in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central grey, the substantia nigra, the raphé nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Eggermann et al. (2001) found its role in exciting cholinergic neurons of the basal forebrain area and no effect on the GABA sleep-promoting neurons of the preoptic area. Liu, van
Antidepressant effects of long photoperiod 20 den Pol and Aghajanian (2002) studied a role of the Orexin neurons on 5-HT in the dorsal raphé nucleus (DRN). They found that the Orexin neurons activate 5-HT by a TTX-insensitive, Na+/K+ nonselective cation current, and local inhibitory GABA inputs to 5-HT cells. This suggests an involvement of the Orexin neurons in arousal system. Yoshida, McCormack, Espana, Crocker, and Scammell (2006) found greater range of connectivity of the Orexin neurons. One of them is from SCN via the subparaventricular zone and dorsomedial nucleus. Gompf and Aston-Jones (2008) studied involvement of the orexin neurons in the wakefulness and behavioral arousal mediated by locus coeruleus. They found that LC’s activity was significantly increased by injection of orexin-A. Dorsomedial hypothalamic neurons preferentially project to the LC and their Fos expression increased when LC impulse activity was high. Bubser et al. (2005) found that orexin cells in the medial lateral hypothalamus/perifornical area are regulated by dopamine. Overall, orexin system integrates circadian and metabolic influences “to regulate the timing and consolidation of behavioral, arousal, motivational and nutritional states (Selbach & Haas, 2006). Reduction in number of orexin neurons in rats (Wister-Kyoto rats) shows depressive characteristics and abnormal sleep (Allard, Tizabi, Shaffery, Trouth, & Manaye, 2004). Animal Model The depressive-like behavior can be assessed by forced swim test (FST). Developed by Porsolt and his colleagues FST has been widely used for a tool for assessing antidepressant activity because immobility shown in FST is considered to be analogous to the hopelessness in depressed patients (Porsolt, LePichon & Jalfre, 1977; Cryan, Markou, & Lucki, 2002; Kobayashi,
Antidepressant effects of long photoperiod 21 Hayashi, Shimamura, Kinoshita, & Murphy, 2008). During FST a rat is placed in a container filled with water so that the rats cannot keep their body above the water by touching the bottom (Gutierrez-Garcia & Contreras, 2009). They are considered immobile when they showed minimum movements to maintain their heads above water (Swiergiel, Leskov, & Dunn, 2008). Questions and discussions have been brought from researchers over interpretation of the immobility shown in FST (Willner, 1984; Borsini & Meli, 1988). However, it has been shown that significant correlation between reduction of immobility time by antidepressants and clinical potency (Willner, 1984). It has been shown that several changes in neurotransmitter levels in the brain during and after FST. Roche, Commons, Peoples, and Valentino (2003) studied effects of swim stress on dorsolateral subregion of the dorsal raphé nucleus of the adult male Sprague Dawley rats. Activation of CRF-R1 receptors on GABA-containing neurons was suggested and led expression of the neuron. This resulted in inhibition of the 5-HT neurons. Engelmann, Ebner, Landgraf and Wotjak (1998) studied release of AVP in SCN in make rats due to ten-minute FST. Short-term increase of AVP was observed (approx. 440%). Since SCN neurons affect and regulate neuroendocrine system, AVP is thought to be involved in rhythmus under stress. External environmental changes may alter mood and trigger development of mood disorder. In SAD, involvement of photoperiod is one of the unique features and, therefore, shortening photoperiod in winter is a candidate for facilitating development of depressive episodes. Since Wistar rats are nocturnal animals, it is thought that the effect of light is reversed. Thus, if people show depression under short photoperiod, rats may show depression under long photoperiod. Therefore, it is hypothesized that long photoperiod may induce depressive-like behavior in rats.
Antidepressant effects of long photoperiod 22 Materials and Methods Subjects Subjects were sixteen male Harlan Sprague Dawley® rats obtained from a supplier at approximately 40 days of age. Eight of the rats were group-housed in normal photoperiod and another eight were group-housed in abnormal photoperiod. The cages were transparent plastic (50 x 39 x 20 cm) with wood shaving bedding, and placed in the animal colony rooms in the Psychology Department at Muskingum College. Under normal photoperiod, light was on at 0800h and off at 2000h (12L/ 12D), and under abnormal photoperiod, light was off at 1000h and on at 1400h (20L/ 4D). Fluorescent lights were used in both conditions and they were ordinary luminance. Tap water and food were available ad lib. Their cages were cleaned once a week. Apparatus A rectangular plastic container (25 x 33 x 51cm) was used for FST. The container was filled with water to a depth of 30cm. Water was maintained at room temperature (18.0-20.0ºC) and changed every session. Procedure The present experiment was approved by Muskingum College Institutional Animal Care and Use Committee. Animals were placed into their respective lighting conditions for 28 days for control group and 22 days for experimental group. After the habituation, FST was conducted on rats. One test consisted of two trials; habituation and test. On day of habituation, each rat was placed in water one by one, and allowed to swim for 15 minutes. After the swimming, they were removed, dried off with paper towels and returned to their home cage. In the following day,
Antidepressant effects of long photoperiod 23 animals were tested. They were placed in apparatus and habituated for 1 minute and then amount of time spent immobile was recorded during the 4 minute test period. Every habituation and test was conducted 90 minutes prior to the dark period. FST started at 1830h for a control group and at 0830h for an abnormal. After each trial, rats were removed from the container and dried with paper towels. Results Time of immobility was approximately 47 seconds on average for the control group while it was 22 seconds in an experimental group. This reduction in mobility was statistically significant, t(14) = 2.673, p = 0.018. There was no difference in weight between a control and experimental group, t(14) = 0.239, p > 0.05. Figure 1 shows difference in time of immobility between the groups. Discussion Contrary to prediction, long photoperiod did not induce depressive-like behavior in rats. Instead, consistent with a previous study on an effect of long photoperiod (14L/10D) by MolinaHernandez and Tellez-Alcantara (2000), a significant decrease in immobility was found and that suggests antidepressant-like effect of long photoperiod. FST is used widely due to its simplicity and yet the result is affected by its settings. Taltavull, Chefer, Shippenberg and Kiyatkin (2003) showed an effect of water temperature in FST. Cold water (25ºC) significantly increased immobility while warm water (37ºC) showed no immobility. They hypothesized that immobility resulted from brain hypothermia. In the present study, difference in temperature between the conditions was considerably small and therefore the difference in immobility was probably not due to water temperature.
Antidepressant effects of long photoperiod 24 Although subjects were only male rats in the present study, it is worthy to note that sexual difference in sensitivity to antidepressants was found in certain mice in FST and some study reported shorter immobility in male than female (Petit-Demouliere, Chenu, & Bourin, 2005). In the present study, those concerns about FST were cleared. However, there are limitations in the present study due to limited facilities, and therefore a few environmental differences between the control and experimental group were indispensable. First of all, rooms where rats were placed could not be identical. The control had bigger space with other rats while experimental group had own small room. Second, experimental group could not be tested in the same room due to a limited space of the room, and therefore it could not avoid influences of novel environment on their behavior. Given considerations above, let us discuss some implications of the anti-depressant effect found in the present study. Numbers of researches to illuminate etiology of SAD have focused on its spectacular features – seasonal recurrence and therapeutic effects of light. Continuation of researches on SAD inspired by these vivid features may give insights on affective disorder, or sadly isolate itself from other major affective disorders. Today, in order to study SAD, DSM helps to identify problems but it is not made to diagnose the origin of dysfunction. Since neural activities, cognitive activities as well as behavioral activities are dynamically mutual and hierarchical, it is vital to examine the unique features of SAD from different dimensions and scales. In this section, the antidepressant effects of light are going to be discussed based on a notion that mood is affected by activities of neurotransmitters. After the invention of FST, it has been modified to be responsive to acute antidepressant treatments such as catecholaminergic agents and 5-HT related compounds (Cryan, Markou, &
Antidepressant effects of long photoperiod 25 Lucki, 2002). Correlation between administration of antidepressants and change in immobility has been reported and it is suggested that change in immobility reflects change in levels of neurotransmitters, although psychological implication of immobility shown in FST has been discussed (Willner, 1984; Borsini & Meli, 1988). Direct evidence of change in neurotransmitters in the brain came from a study by Kobayashi, Hayashi, Shimamura, Kinoshita, & Murphy (2008). Their microdialysis study showed correlation between efficacy of FST and increased level of DA in prefrontal cortex of mice. The result of the present study implies that altering photoperiod can affect levels of the neurotransmitters, especially DA. It is known that DA neurons in the prefrontal cortex are projected from ventral tegmental area (VTA). This area is projected by lateral hypothalamic orexin neurons (LHA). According to Saper, Scammell, and Lu (2005), LHA is projected by dorsomedial hypothalamus (DMH). It is suggested that DMH integrates information from SCN with external non-photic cues to provide flexible adaptation of behavioral and physiological cycle. A study by Gonzalez and Aston-Jones (2008) showed important influence of light to some fundamental nuclei. Light deprivation for 6 weeks resulted in apoptosis or damages of neurons in locus coeruleus, raphé nucleus, and ventral tegmental area. Those areas are indirectly projected from SCN through DMH, and dendritic regions of locus coeruleus are also projected through medial preoptic area (Deurveilher & Semba, 2005). These studies show that indirect projection of SCN to dopaminergic neurons in PFC may play a role in reduction of immobility. In conclusion, the present study suggests that SCN overly activates some hypothalamic regions under long photoperiod that are a part of the arousal/wake-regulatory system and cognitive functions. It is unknown whether over activation of these nuclei has antidepressant
Antidepressant effects of long photoperiod 26 effects. However, irregularity of these systems has been clearly seen in depressive patients. Therefore, it implies dysfunctional integration of those hypothalamic areas responding to external light conditions may play some roles in certain mood disorders. It is noteworthy that this study was done under ordinary luminance. Therefore, it makes people wonder how artificial lights surrounding us can affect our affective state.
Antidepressant effects of long photoperiod 27 References Abrahamson, E. E., & Moore, R. Y. (2001). Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Research, 916, 172-191. Allard, J. S., Tizabi, Y., Shaffery, J. P., Trouth, C. O., & Manaye, K. (2004). Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. Neuropeptides, 38, 311-315. American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders (Ed. 4). APA. Aston-Jones, G., Chen, S., Zhu, Y., & Oshinsky, M. L. (2001). Nature Neuroscience, 4(7), 732738. Berson, D. M., Dunn, F. A., & Takao, M. (2002). Phototransduction by retinal ganglion cells that set the circadian clock. Science, 295, 1070-1073. Benabid, N., Mesfioui, A. & Ouichou, A. (2008). Effects of photoperiod regimen on emotional behavior in two tests for anxiolytic activity in wistar rat. Brain Research Bulletin, 75, 5359. Bhatnagar, S., & Dallman, M. F. (1999). The paraventricular nucleus of the thalamus alters rhythms in core temperature and energy balance in a state-dependent manner. Brain Research, 851, 66-75. Borsini, F. & Meli, A. (1988). Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology, 94, 147-160. Briaud, S. A., Zhang, B. L., & Sannajust, F. (2004). Continuous light exposure and sympathectomy suppress circadian rhythm of blood pressure in rats. Journal of Caudiovasc Pharmacol Therapeut, 9(2), 97-105.
Antidepressant effects of long photoperiod 28 Bubser, M., Fadel, J. R., Jackson, L. L., Meador-Woodruff, J. H., Jing, D., & Deutch, A. Y. (2005). Dopaminergic regulation of orexin neurons. European J. of Neuroscience. 21, 2993-3001. Chou, T. C., Bjorkum, A. A., Gaus, S. E., Lu, J., Scammell, T. E., & Saper, C. B. (2002). Afferents to the ventrolateral preoptic nucleus. The Journal of Neuroscience, 22(3), 977990. Cohen, R. M., Gross, M., Nordahl, T. E., Semple, W. E., Oren, D. A., & Rosenthal, N. (1992). Preliminary data on the metabolic brain pattern of patients with winter seasonal affective disorder. Arch. Gen. Psychiatry, 49(7), 545-552. Cryan, J.F., Markou, A., & Lucki, I. (2002). Assessing antidepressant activity in rodents: recent development and future needs. TRENDS in Pharmacological Science, 23(5), 238-245. Damasio, A. R. (1999). The feeling of what happens: body and emotion in the making of consciousness. Harcourt Brace & Company. Dalla, C., Antoniou, K., Drossopoulou, G., Xagoraris, M., Kokras, N., Sfikakis, A., & Papadopoulou-Daifoti, Z. (2005). Chronic mild stress impact: are females more vulnerable? Neuroscience, 135(3), 703-714. Danese, A. & Pariante, C. M. (2008). Mood (affective) disorders. Medicine, 36(8), 410-414. Deurveilher, S. & Semba, K. (2005). Indirect projections from the suprachiasmatic nucleus to major arousal-promoting cell groups in rat: implications for the circadian control of behavioral state. Neuroscience, 130, 165-183. Eastman, C. I., Young, M. A., Fogg, L. F. Liu, L., & Meaden, P. M. (1998). Bright light treatment of winter depression. Arch Gen OPsychiatry, 55, 883-889. Eggermann, E., Serafin, M., Bayer, L., Machard, D., Saint-Mleux, B., Jones, B. E., &
Antidepressant effects of long photoperiod 29 Mühlethaler, M. (2001). Orexins/hypocretins excite basal forebrain cholinergic neurons. Neuroscience, 108(2), 177-181. Einat, H., Kronfeld-Schor, N., & Eilam, D. (2006). Sand rats see the light: Short photoperiod induces a depression-like response in a diurnal rodent. Behavioral Brain Research, 173, 153-157. Elliot J. A. (1976). Circadian rhythms and photoperiodic time measurement in mammals. Federation proceedings, 35(12), 2339-2346. Engelmann, M., Ebner, K., Landgraf, R., & Wotjak, C. T. (1998). Swim stress triggers the release of vasopressin within the suprachiasmatic nucleus of male rats. Brain Research, 792, 343-347. Foster, R. G. & Kreitaman, L. (2004). Rhythms of life. New Haven, CT: Yale University Press. Freedman, M. S., Lucas, R. J., Soni, B., von Schantz, M., Munoz, M., David-Gray, Z., Foster, R. (1999). Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science, 284, 502-504. Giedke, H. & Schwärzler, F. (2002). Therapeutic use of sleep deprivation in depression. Sleep Medicine Reviews, 6(5), 361-377. Gomph, H. S. & Aston-Jones, G. (2008). Role of orexin input in the diurnal rhythm of locus coeruleus impulse activity. Brain Research. 1224, 43-52. Gonzalez, M. M. C. & Aston-Jones, G. (2008). Light deprivation damages monoamine neurons and produces a depressive behavior phenotype in rats. Proceedings of the National Academy of Sciences, 105(12), 4898-4903. Green, M. J., Cahill, C. M., & Malhi, G. S. (2007). The cognitive and neurophysiological basis of emotion dysregulation in bipolar disorder. Journal of Affective Disorders, 103, 29-42.
Antidepressant effects of long photoperiod 30 Gutierrez-Garcia, A. G. & Contreras, C. M. (2009). Stressors can affect immobility time and response to imipramine in the rat forced swim test. Pharmacology, Biochemistry and Behavior, 91, 542-548. Gvilia, I., Xu, F., McGinty, D., & Szymusiak, R. (2006). Homeostatic regulation of sleep: a role for preoptic area neurons. Journal of Neuroscience. 26(37), 9426-9433. Hankins, M. W., Peirson, S. N., Foster, R. G. (2007). Melanopsin: an exciting photopigment. TRENDS in Neuroscience, 31(1), 27-36. Hebert, M., Beattie, C. W., Tam, E. M., Yatham, L. N., & Lam, R. W. (2004). Electroetinography in patients with winter seasonal affective disorder. Psychiatry Research, 127, 27-34. Heideman, P. D. & Bronson, F. H. (1993). Sensitivity of Syrian Hamsters (Mesocricetus auratus) to amplitudes and rates of photoperiodic change typical of the tropics. Journal of Biological Rhythms, 8(4), 325-337. Heils, A., Teufel, A., Petri, S., Stöber, G., Riederer, P., Bengel, D., & Lesch, P. (1996). Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry, 66,2621-2624. Hyun, L. S., Beob, L. Y., and Barry, W. D. (2005). Retrograde study of projections from the tuberomammillary nucleus to the dorsal raphé and the locus coeruleus in the rat. Brain Research, 1043, 65-75. Inagaki, N., Toda, K., Taniuchi, I., Panula, P., Yamatodani, A., Tohyama, M., Watanabe, T., & Wada, H. (1990). An analysis of histaminergic efferents of the tuberomammillary nucleus to the medial preoptic area and inferior colliculus of the rat. Exp Brain Research, 80, 374380.
Antidepressant effects of long photoperiod 31 Jacobsen, F. M., Wehr, T. A., Sack, D. A., James, S. P., & Rosenthal, N. E. (1984). Seasonal affective disorder: A review of the syndrome and its public health implications. American Journal of Public Health, 77(1), 57-60. Kalasbeek, A., Buijs, R. M., van Heerikhuize, J. J., Arts, M., & van Der Woude, T. P. (1992). Vasopressin-containing neurons of the suprachiasmatic nuclei inhibit corticosterone release. Brain Research, 580, 62-67. Kirouac, G. J., Parsons, M. P., & Li, S. (2005). Orexin (hypocretin) innervation of the paraventricular nucleus of the thalamus. Brain Research, 1059, 179-188. Kobayashi, T., Hayashi, E., Shimamura, M., Kinoshita, M., & Murphy, N.P. (2008). Neurochemical responses to antidepressants in the prefrontal cortex of mice and their efficacy in preclinical models of anxiety-like and depression-like behavior: a comparative and correlational study. Psychopharmacology, 197, 567-580. Lam, R. W., Tam, E. M., Yatham, L. N., Shiah, I-S. & Zis, A. P. (2001). Seasonal depression The dual vulnerability hypothesis revisited. Journal of Affective Disorders, 63:123-132. Lane, R. D. (2006). Theory of emotional awareness and brain processing of emotion. International Congress Series, 1287, 116-121. Leak, R. K. & Moore, R. Y. (1997). Identification of retinal ganglion cells projecting to the lateral hypothalamic area of the rat. Brain Research, 770, 105-114. Lewy, A. J., Sack, R. L., Miller, L. S., & Hoban, T. M. (1987). Antidepressant and circadian phase-shifting effects of light. Science., 235, 352. Lewy, A. J., Bauer, V. K., Cutler, N. L., Sack, R. L., Ahmed, S., Thomas, K., H., Blood, M. L., & Latham Jackson, J. M. (1998). Morning vs evening light treatment of patients with winter depression. Arch Gen Psychiatry, 55, 890-896.
Antidepressant effects of long photoperiod 32 Liu, R-J., van den Pol, A. N., & Aghajanian, G. K. (2002). Hypocretins (orexins) regulate serotonin neurons in the dorsal raphé nucleus by excitatory direct and inhibitory indirect actions. Journal of Neuroscience, 22(21), 9453-9464. Lu, J., Jhou, C., & Saper, C. B. (2006). Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter. Journal of Neuroscience, 26(1), 193-202. Lu, J., Shiromani, P., & Saper, C. B. (1999). Retinal input to the sleep-active ventrolateral preoptic nucleus in the rat. Neuroscience, 93(1), 209-214. Magrusson, A. & Partonen, T. (2005). The diagnosis, symptomatology, and epidemiology of seasonal affective disorder. CNS Spectrums, 10(8), 625-634. Martiny, K., Lunde, M., Unden, M., Dam H., & Bech, P. (2005). Adjustive bright light in nonseasonal major depression: results from patient-reported symptom and well-being scales. Acta Psychiatr Scand, 111, 453-459. Meesters, Y., Beersma, D. G. M., Bouhuys, A. L., & van der Hoofdakker, R. H. (1999). Prophylactic treatment of seasonal affective disorder (sad) by using light visors: bright white or infrared light? Biological Psychiatry, 46,239-246. Meyer, J. H., Ginovart, N., Boovarriwala, A., Sagrati, S., Hussey, D., Garcia, A., Young, T., Praschak-Rieder, N., Wilson, A. A., & Houle, S. (2006). Elevated monoamine oxidase a level in the brain. Arch Gen Psychiatry, 63, 1209-1216. Morin, L. P. & Blanchard J. (1991). Depletion of brain serotonin by 5,7-DHT modifies hamster circadian rhythm response to light. Brain Research, 566, 173-185. Molina-Hernandez, M & Tellez-Alcantara, P. (2000). Long photoperiod regimen may produce antidepressant actions in the male rat. Prog. Neuro-Psychoparmacol & Biol. Pscychiat, 24, 105-116.
Antidepressant effects of long photoperiod 33 Murray, G., Allen, N. B., & Trinder, J. (2001). A longitudinal investigation of seasonal variation in mood. Chronobiology International, 18(15), 875-891. Nathan, P. J., Burrows, G. D., & Norman, T. R. (1999). Melatonin sensitivity to dim white light in affective disorders. Neuropsychopharmacology, 21(3), 408-413. Neumeister, A., Konstantinidis, A., Stastny, J., Schwarz, M. J., Vitouch, O., Willeit, M., Praschak-Rieder, N., Zach, J., Zwaan, M., Bondy, B., Ackenheil, M. & Kasper, S. (2002). Association between serotonin transporter gene promoter polymorphisim (5httlpr) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression. Arc Gen Psychiatry, 59, 613-620. Neumeister, A., Turner, E. H., Matthews, J. R., Postolache, T. T., Barnett, R. L., Rauh, M., Vetticad, R. G., Kasper, S., & Rosenthal, N. E. (1998). Effects of tryptophan depletion vs catecholamine depletion in patients with seasonal affective disorder in remission with light therapy. Arch Gen Psychiatry, 55, 524-530. Partonen, T. (1996). Dopamine and circadian rhythms in seasonal affective disorder. Medical Hypothesis, 47, 191-192. Partnen, T., Vakkuri, O., & Lonnqvist, J. (1997). Supression of melatonin secretion by bright light in seasonal affective disorder. Biol Psychiatry, 42, 509-513. Partonen, T., Vakkuri, O., & Lönnqvist, J. (1997). Suppression of melatonin secretion by bright light in seasonal affective disorder. Biol. Psychiatry, 42, 509-513. Petit-Demouliere, B., Chenu, F., & Bourin, M. (2005). Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology, 177, 245-255. Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, C., Sutcliffe, J. G., & Kilduff, T. S. (1998). Neurons containing hypocretin (orexin) project to multiple neuronal systems.
Antidepressant effects of long photoperiod 34 Journal of Neuroscience, 18(23), 9996-10015. Porcelli, A. J., Cruz, D., Wenberg, K., Patterson, M. D., Biswal, B. B., & Rypma, B. (2008). The effects of acute stress on human prefrontal working memory systems. Physiology & Behavior, 95, 282-289. Porsolt, R.D., LePichon, M., & Jalfre, M.J. (1977). Depression: a new animal model sensitive to antidepressant treatments. Nature 266, 730-732. Prendergast, B. J. & Kay, L. M. (2008). Affective and adrenocorticotrophic responses to photoperiod in wistar rats. Journal of Neuroendocrinology, 20, 261-267. Prendergast, B. J. & Randy, J. N. (2005). Affective responses to changes in day length in siberian hamsters (phodopus sungorus). Psychoneuroendocrinology, 30, 438-452. Puerto, A., & Mahia, J. (2006). Lesions of tuberomammillary nuclei induce differential polydipsic and hyperphagic effects. European Journal of Neuroscience, 23, 1321-1331. Raadsheer, F. C., Hoogendijk, W. J. G., Stam, F. C., Tilders, F. J. H., & Swaab, D. F. (1994). Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology, 60, 436-444. Roche, M., Commons, K. G., Peoples, A., & Valentino, R. J. (2003). Circuitry underlying regulation of the serotonergic system by swim stress. Journal of Neuroscience, 23(3), 970-977. Rosenthal, N. E., Sack, D. A., Gillin, J. C., Lewy, A. J., Goodwin, F. K., Davenport, Y., Mueller, P. S., Newsome, D. A., & Wehr, T. A. (1984). Seasonal affective disorder- a description of the syndrome and preliminary findings with light therapy. Arch. Gen. Psychology, 41, 72-80.
Antidepressant effects of long photoperiod 35 Roybal, K., Theobold, D., Graham, A., DiNieri, J. A., Russo, S., Krishnan, V., Chakravarty, S., Peevey, J., Oehrlein, N., Birnbaum, S., Vitaterna, M. H., Orsulak, P., Takahashi, J. S., Nestler, E. J., Carlezon, Jr., W. A., & McClung, C. A. (2007). Mania-like behavior induced by disruption of clock. Proceedings of the National Academy of Science, 104(15), 6406-6411. Saint-Mleux, B., Bayer, L., Eggermann, E., Jones, B. E., Mühlethaler, M., & Serafin M. (2007). Suprachiasmatic modulation of noradrenaline release in the ventrolateral preoptic nucleus. Journal of Neuroscience, 27(24), 6412-6416. Saper, C. B., Lu, J., Chou, T. C., & Gooley, J. (2005). The hypothalamic integrator for circadian rhythms. TRENDS in Neuroscience, 28(3), 152-157. Saper, C. B., Scammell, T. E., & Lu, J. (2005). Hypothalamic regulation of sleep and circadian rhythms. Nature, 437, 1257-1263. Selbach, O. & Haas, H. (2006). Hypocretins: the timing of sleep and waking. Chronobiology International, 23(1&2), 63-70. Sharma, V. M., & Panwar, M. R. (1987). Variations in mental performance under moderate cold stress. International Journal of Biometeorology, 31(1), 85-91. Sherin, J. E., Elmquist, J. K., Torrealba, F., & Saper, C. B. (1998). Innervation of histaminergic tuberomammillary neurons by gabaergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. Journal of Neuroscience, 18(12), 4705-4721. Shi, J., Wittke-Thompson, J. K., Badner, J. A., Hattori, E., Potash, J. B., Willour, V. L., McMahon, F. J., Gershon, E. S., & Liu C. (2008). Clock genes may influence bipolar disorder susceptibility and dysfunctional circadian rhythm. Am J Med Genetics Part B: Neuropsychiatr Genet, 147(B), 1047-1055.
Antidepressant effects of long photoperiod 36 Sigmon, S. T., Whitcomb-Smith, S., Boulard, N. E., Pells, J. J., Hermann, B. A., Edenfield, T. M., LaMattina, S. M., & Schartel, J. G. (2007). Seasonal reactivity: attentional bias and psychophysiological arousal in seasonal and nonseasonal depression. Cognitive Therapy and Research, 31, 619-638. Soni, B. G., Philp, A. R., & Foster, R. G. (1998). Novel retinal photoreceptors. Nature, 394, 2728. Swaab, D. F., Bao, A.-M., & Lucassen, P. J. (2005). The stress system in the human brain in depression and neurodegeneration. Aging Research Reviews, 4, 141-194. Swiergiel, A. H., Leskov, I. L., & Dunn, A. J. (2008). Effects of chronic and acute stressors and crf on depression-like behavior in mice. Behavioral Brain Research, 186, 32-40. Taltavull, J. F., Chefer, V. I., Shippenberg, T. S., & Kiyatkin, E. A. (2003). Severe brain hypothermia as a factor underlying behavioral immobility during cold-water forced swim. Brain Research, 975, 244-247. Teng, C. T., Akerman, D., Cordas, T. A., Kasper, S., Vieira, A. H. G. (1995). Seasonal affective disorder in a tropical country: a case report. Psychiatry Research, 56, 11-15. Terman, M., Terman, J. S., Quitkin, F. M., Cooper, T. B., Lo, E. S., Gorman, J. M., Stewart, J. W., & McGrath, P. J. (1988). Response of the melatonin cycle to phototherapy for seasonal affective disorder. Journal of Neural Transmission, 72, 147-165. Tsai, J-F., Hsiao, S., & Wang, S-Y. (2007). Infrared irradiation has potential antidepressant effect. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 31, 1397-1400. Turek, F. W. & Gillette, M. U. (2004). Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Medicine, 5, 523-532. Uschakov, A., Gong, H., McGinty, D., & Szymusiak, R. (2007). Efferent projections from the
Antidepressant effects of long photoperiod 37 median preoptic nucleus to sleep- and arousal-regulatory nuclei in the rat brain. Neuroscience, 150, 104-120. Watson, S., & Mackin, P. (2006). HPA axis function in mood disorders. Psychiatry, 5, 166-170. Wehr, T. A., Duncun, W. C., Sher, L., Aeschbach, D., Schwartz, P. J., Turner, E. H., Postolache, T. T., & Rosenthal, N. E. (2001). A circadian signal of change of season in patients with seasonal affective disorder. Arch Gen Psychiatry, 58, 1108-1114. Wilner, P. (1984). The validity of animal models of depression. Psychopharmacology, 83, 1-16. World Health Organization. (2007). The ICD-10 classification of mental and behavioral disorders. Retrieved December 11, 2008, from http://www.who.int/classifications/apps/icd/icd10online/ Yi, S. J., & Baram, T. (1994). Corticotropin-releasing hormone mediates the response to cold stress in the neonatal rat without compensatory enhancement of the peptide’s gene expression. Endocrinology, 135, 2364-2368. Yoshida, K., McCormack, S., Espana, R. A., Crocker, A., & Scammell, T. E. (2006). Afferents to the orexin neurons of the rat brain. Journal of Comparative Neurology, 494, 845-861. Zhou, JN., Riemersma, R. F., Unmehopa, U. A., Hoogendijk, W. J. G., van Heerikhuize, J. J., Hofman, M. A., & Swaab, D. F. (2001). Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus in depression. Arch Gen Psychiatry, 58, 655-662.
Antidepressant effects of long photoperiod 38 Table 1 Difference in Neurons of SCN between the Subdivisions Core Contents
Shell
GABA
GABA
calbindin (CARB)
CARB
vasoactive intestinal polypeptide (VIP)
AVP
calretinin (CALR)
angiotensin II (AII)
gastrin releasing peptide (GRP)
met-enkephalin (mENK)
neurotensin (NT) Input
neuropeptide Y (NPY)
galanin (GAL)
5-HT
VIP
Antidepressant effects of long photoperiod 39 Table 2 Afferent and efferent projections of wake-active dopaminergic cells in MPN Projection
Input
medial prefrontal cortex
medial prefrontal cortex
VLPO
VLPO
lateral hypothalamic orexin cells
orexin cells
pontine LDT cholinergic thalamus
pontine LDT cholinergic cells
LC
LC noradrenergic cells
Midline & intraminar thalamus Basal forebrain cholinergic neurons
Antidepressant effects of long photoperiod 40 Figure Caption Figure One. Mean time of immobility for the control and experimental group.
Antidepressant effects of long photoperiod 41 Figure 1
50.0
45.0
Mean Time of Immobility (sec.)
40.0
35.0
30.0
*
25.0
20.0
15.0
10.0
5.0
0.0 Control
Abnormal Light Cycle
