Lactation is not required for maintaining maternal care and active coping responses in chronically stressed postpartum rats: Interactions between nursing demand and chronic variable stress.

Women who do not breastfeed or discontinue breastfeeding early are more likely to develop postpartum depression (PPD) and stress is a significant risk factor for depression, including PPD. Using a rat model, we investigated whether the absence of nursing would increase the susceptibility to chronic stress-related behavioral and neural changes during the postpartum period. Adult female rats underwent thelectomy (thel; removal of teats), sham surgery, or no surgery (control) and were paired with males for breeding. All litters were rotated twice daily until postpartum day (PD) 26. Sham rats served as surrogates for thel litters, yielding a higher nursing demand for sham rats. Concurrently, rats received either no stress or chronic variable stress until PD 25. Rats were observed for maternal behaviors and tested in a series of tasks including open field, sucrose preference, and forced swim. We used immunohistochemistry (IHC) for doublecortin (DCX; to label immature neurons) or for mineralocorticoid receptor (MR). Contrary to our expectations, non-nursing thel rats were resistant to the effects of stress in all dependent measures. Our data indicate that even in chronic adverse conditions, nursing is not required for maintaining stable care to offspring or active coping responses in an acutely stressful task. We discuss the possible role of offspring contact and consider future directions for biomedical and clinical research. In rats with high nursing demand, however, chronic stress increased immobility, hippocampal neurogenesis, and MR expression (largely in opposition to the effects of stress in rats with typical nursing demand). We discuss these patterns in the context of energetics and allostatic load. This research highlights the complexity in relationships between stress, nursing, and neurobehavioral outcomes in the postpartum period and underscores the need for additional biomedical and clinical research geared toward optimizing treatments and interventions for women with PPD, regardless of breastfeeding status. SIGNIFICANCE STATEMENT: The goal of this research was to determine how the absence of nursing and higher nursing demand impact stress-coping behaviors and neural changes associated with chronic stress in order to disentangle the complex interplay of factors that contribute to psychological illness during the postpartum period.

Rotated nursing environment with underfeeding: A form of early-life adversity with sex- and age-dependent effects on coping behavior and hippocampal neurogenesis.

We investigated how a unique form of early-life adversity (ELA), caused by rotated nursing environment to induce underfeeding, alters anxiety-like and stress-coping behaviors in male and female Sprague Dawley rats in adolescence and adulthood. Adult female rats underwent either thelectomy (thel; surgical removal of teats), sham surgery, or no surgery (control) before mating. Following parturition, litters were rotated between sham and thel rats every 12 h to generate a group of rats that experienced ELA (rotated housing, rotated mother, and 50% food restriction) from postnatal day 0 to 26. Control litters remained with their natal, nursing dams. Regardless of age and sex, ELA reduced activity in the periphery of the open field. ELA increased immobility in the forced swim test, particularly in adults. We used doublecortin immunohistochemistry to identify immature neurons in the hippocampus. ELA increased the number and density of immature neurons in the dentate gyrus of adolescent males (but not females) and reduced the density of immature neurons in adult males (but not females). This research indicates that a unique form of ELA alters stress-related passive coping and hippocampal neurogenesis in an age- and sex-dependent manner.

Maternal experience and adult neurogenesis in mammals: Implications for maternal care, cognition, and mental health.

The transition to motherhood encompasses physiological and behavioral adaptations essential for the initiation and maintenance of offspring care and feeding and includes widespread changes throughout the brain. The growth of new neurons occurs across the lifespan in distinct regions of mammalian brains and changes dynamically across reproductive events in female mammals. The subventricular zone (SVZ) and dentate gyrus (DG) of the hippocampus undergo high rates of neurogenesis in adulthood and are sensitive to hormonal fluctuations. Pregnancy and the postpartum period are associated with increased cell proliferation in the SVZ and interneuron survival in the olfactory bulb. In mice, peripartum prolactin signaling mediates SVZ neurogenesis and is important for enhanced olfactory recognition of offspring and maternal care. In contrast, cell proliferation and immature neuron survival decrease in the DG during the postpartum period. High baseline glucocorticoid concentrations suppress hippocampal neurogenesis, potentially representing an energetic trade-off accompanying a reduced need for spatial navigation early postpartum. In women, hippocampal volume decline during pregnancy and partial recovery during the postpartum period could contribute to the risk of psychiatric illness. New evidence indicates that the dorsal raphe nucleus (DR) is an additional site for adult neurogenesis sensitive to reproductive experience and offspring contact. In this review, we discuss the initial and lasting impact of maternal experience on adult neurogenesis. Because neurogenesis has been implicated in a variety of psychiatric and neurodegenerative illnesses, understanding how reproductive experience alters new neuron production in maternal mammals has far-reaching implications for women's health and wellness across the lifespan.

High nursing demand reduces depression-like behavior despite increasing glucocorticoid concentrations and reducing hippocampal neurogenesis in late postpartum rats.

Approximately 15% of women who give birth develop postpartum depression (PPD), and the risk is greater in women who do not breastfeed or who cease breastfeeding early. In some women, early cessation or absence of breastfeeding precedes PPD, but the neuroendocrine mechanisms of this relationship are unknown. We tested whether nursing demand would alter behavioral and endocrine endpoints relevant for depression in postpartum rats. Adult female Sprague-Dawley rats underwent thelectomy (thel; removal of teats), sham surgery (sham), or no surgery (control). Litters were rotated between thel and sham rats every 12 h, yielding a higher nursing burden for sham rats. We investigated behavior in the forced swim test (FST), open field test, and sucrose preference test, and serum corticosterone (CORT) concentrations. Because the hippocampus changes structurally in depression and with maternal experience, we investigated cell proliferation using Ki-67 and hippocampal neurogenesis and immature neuron development using doublecortin (DCX) immunohistochemistry. Sham rats spent less time immobile in the FST compared with control and thel rats. Sham rats also had higher CORT concentrations and fewer Ki-67 cells. Thel rats had more DCX-expressing cells and a greater proportion of mature DCX-expressing cells compared with control and sham rats. These data suggest that greater nursing demand reduces stress-related behavioral responses despite increasing CORT concentrations and suppressing hippocampal neurogenesis. This work is an important step in identifying how lactation buffers behavioral responses to stress and reorganizes stress-related neural circuitry and is crucial for identifying mechanisms of postpartum psychiatric illnesses.

Voluntary running influences the efficacy of fluoxetine in a model of postpartum depression.

Postpartum depression affects approximately 15% of mothers. Unfortunately, treatment options for postpartum depression are limited. Pharmacological antidepressants such as fluoxetine (FLX) can be controversial due to inconclusive evidence of efficacy during the postpartum and concerns of neonatal exposure to antidepressants. Alternatively, non-pharmacological antidepressants such as exercise may be less controversial but its efficacy in postpartum depression is unclear. To investigate this, we treated rat dams daily with high levels of corticosterone (CORT; 40 mg/kg), to induce a depressive-like phenotype, or oil (vehicle for CORT) during the postpartum period. Within the oil and CORT conditions, four additional antidepressant conditions were created: 1. FLX (10 mg/kg) + exercise (voluntary access to running wheel); 2. FLX + no exercise; 3. Saline (vehicle for FLX) + exercise; 4. Saline + No exercise. We examined maternal care, depressive-like and anxiety-like behavior, stress reactivity, and hippocampal neurogenesis and dams were categorized as "high running" or "low running." FLX treatment, alone or with high running, prevented CORT-induced disruptions in maternal care. As expected, CORT increased depressive-like behavior but exercise, regardless of running amount, reduced depressive-like behavior. Intriguingly, FLX, but not CORT, increased anxiety-like behavior, which was not mitigated by concurrent exercise. FLX treatment slightly but significantly facilitated serum CORT recovery after forced swim stress. CORT and FLX alone reduced neurogenesis, while exercise coupled with FLX increased density of doublecortin-expressing cells. High running increased density of doublecortin-expressing cells (immature neurons) in comparison to controls. Collectively, these findings indicate that FLX and exercise reverse different endophenotypes of depression in dams, which has translational implications for surveying treatment options of postpartum depression.

Sex-dependent effects of maternal corticosterone and SSRI treatment on hippocampal neurogenesis across development.

BACKGROUND: Postpartum depression affects approximately 15% of mothers and represents a form of early life adversity for developing offspring. Postpartum depression can be treated with prescription antidepressants like fluoxetine (FLX). However, FLX can remain active in breast milk, raising concerns about the consequences of neonatal FLX exposure. The hippocampus is highly sensitive to developmental stress, and males and females respond differently to stress at many endpoints, including hippocampal plasticity. However, it is unclear how developmental exposure to FLX alters the trajectory of hippocampal development. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum depression) and concurrent FLX on hippocampal neurogenesis in male and female offspring. METHODS: Female Sprague-Dawley rat dams were treated daily with either CORT or oil and FLX or saline from postpartum days 2-23. Offspring were perfused on postnatal day 31 (pre-adolescent), postnatal day 42 (adolescent), and postnatal day 69 (adult). Tissue was processed for doublecortin (DCX), an endogenous marker of immature neurons, in the dorsal and ventral hippocampus. RESULTS: Maternal postpartum CORT reduced density of DCX-expressing cells in the dorsal hippocampus of pre-adolescent males and increased it in adolescent males, suggesting that postpartum CORT exposure disrupted the typical progression of the density of DCX-expressing cells. Further, among offspring of oil-treated dams, pre-adolescent males had greater density of DCX-expressing cells than pre-adolescent females, and maternal postpartum CORT prevented this sex difference. In pre-adolescent females, maternal postpartum FLX decreased the density of DCX-expressing cells in the dorsal hippocampus compared to saline. As expected, maternal CORT reduced the density of DCX-expressing cells in adult female, but not male, offspring. The combination of maternal postpartum CORT/FLX diminished density of DCX-expressing cells in dorsal hippocampus regardless of sex or age. CONCLUSIONS: These findings reveal how modeling treatment of postpartum depression with FLX alters hippocampal neurogenesis in developing offspring differently depending on sex, predominantly in the dorsal dentate gyrus and earlier in life.

Testosterone has antidepressant-like efficacy and facilitates imipramine-induced neuroplasticity in male rats exposed to chronic unpredictable stress.

Hypogonadal men are more likely to develop depression, while testosterone supplementation shows antidepressant-like effects in hypogonadal men and facilitates antidepressant efficacy. Depression is associated with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and testosterone exerts suppressive effects on the HPA axis. The hippocampus also plays a role in the feedback regulation of the HPA axis, and depressed patients show reduced hippocampal neuroplasticity. We assessed the antidepressant-like effects of testosterone with, or without, imipramine on behavioral and neural endophenotypes of depression in a chronic unpredictable stress (CUS) model of depression. A 21-day CUS protocol was used on gonadectomized male Sprague-Dawley rats treated with vehicle, 1mg of testosterone propionate, 10mg/kg of imipramine, or testosterone and imipramine in tandem. Testosterone treatment reduced novelty-induced hypophagia following CUS exposure, but not under non-stress conditions, representing state-dependent effects. Further, testosterone increased the latency to immobility in the forced swim test (FST), reduced basal corticosterone, and reduced adrenal mass in CUS-exposed rats. Testosterone also facilitated the effects of imipramine by reducing the latency to immobility in the FST and increasing sucrose preference. Testosterone treatment had no significant effect on neurogenesis, though the combination of testosterone and imipramine increased PSA-NCAM expression in the ventral dentate gyrus. These findings demonstrate the antidepressant- and anxiolytic-like effects of testosterone within a CUS model of depression, and provide insight into the mechanism of action, which appears to be independent of enhanced hippocampal neurogenesis.

Parity modifies the effects of fluoxetine and corticosterone on behavior, stress reactivity, and hippocampal neurogenesis.

The postpartum confers considerable risk for developing depression. Depressed patients have elevated cortisol concentrations and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback. Chronic stress or corticosterone (CORT) induces a depressive-like phenotype in rodents, including during the postpartum. The present study examined whether nulliparous and postpartum rats were differentially vulnerable to chronic high CORT and whether fluoxetine (FLX) would differentially alter the brain, behavior, and neuroendocrine function depending on reproductive experience. Nulliparous and postpartum female Sprague-Dawley rats were divided into 4 groups that received 21 d of injections of CORT or oil plus FLX or saline. CORT reduced maternal behaviors whereas FLX reversed CORT-induced decreases in maternal care. CORT increased immobility in the forced swim test (FST), but FLX did not significantly alter immobility in either nulliparous or postpartum rats. Dams spent less time immobile and had lower CORT concentrations after the FST compared with nulliparae, indicating that aspects of the postpartum period may provide resilience against a depressive-like phenotype. Both CORT and parity reduced neurogenesis (doublecortin expression) in the dentate gyrus. FLX-treated rats had lower CORT concentrations following the FST and more immature neurons, but only in the nulliparous, and not postpartum, groups. These data suggest that the postpartum may inherently protect against some deleterious effects of high CORT but also confer resistance to the neurogenic and endocrine effects of FLX. Our findings are important for understanding how females in different reproductive states respond to glucocorticoids and antidepressants.

Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis.

Postpartum depression (PPD) affects approximately 15% of mothers, disrupts maternal care, and can represent a form of early life adversity for the developing offspring. Intriguingly, male and female offspring are differentially vulnerable to the effects of PPD. Antidepressants, such as fluoxetine, are commonly prescribed for treating PPD. However, fluoxetine can reach offspring via breast milk, raising serious concerns regarding the long-term consequences of infant exposure to fluoxetine. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum stress/depression) and concurrent maternal postpartum fluoxetine on behavioral, endocrine, and neural measures in adult male and female offspring. Female Sprague-Dawley dams were treated daily with either CORT or oil and fluoxetine or saline from postnatal days 2-23, and offspring were weaned and left undisturbed until adulthood. Here we show that maternal postpartum fluoxetine increased anxiety-like behavior and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback in adult male, but not female, offspring. Furthermore, maternal postpartum fluoxetine increased the density of immature neurons (doublecortin-expressing) in the hippocampus of adult male offspring but decreased the density of immature neurons in adult female offspring. Maternal postpartum CORT blunted HPA axis negative feedback in males and tended to increase density of immature neurons in males but decreased it in females. These results indicate that maternal postpartum CORT and fluoxetine can have long-lasting effects on anxiety-like behavior, HPA axis negative feedback, and adult hippocampal neurogenesis and that adult male and female offspring are differentially affected by these maternal manipulations.

Alcohol and pregnancy: Effects on maternal care, HPA axis function, and hippocampal neurogenesis in adult females.

Chronic alcohol consumption negatively affects health, and has additional consequences if consumption occurs during pregnancy as prenatal alcohol exposure adversely affects offspring development. While much is known on the effects of prenatal alcohol exposure in offspring less is known about effects of alcohol in dams. Here, we examine whether chronic alcohol consumption during gestation alters maternal behavior, hippocampal neurogenesis and HPA axis activity in late postpartum female rats compared with nulliparous rats. Rats were assigned to alcohol, pair-fed or ad libitum control treatment groups for 21 days (for pregnant rats, this occurred gestation days 1-21). Maternal behavior was assessed throughout the postpartum period. Twenty-one days after alcohol exposure, we assessed doublecortin (DCX) (an endogenous protein expressed in immature neurons) expression in the dorsal and ventral hippocampus and HPA axis activity. Alcohol consumption during pregnancy reduced nursing and increased self-directed and negative behaviors, but spared licking and grooming behavior. Alcohol consumption increased corticosterone and adrenal mass only in nulliparous females. Surprisingly, alcohol consumption did not alter DCX-expressing cell density. However, postpartum females had fewer DCX-expressing cells (and of these cells more immature proliferating cells but fewer postmitotic cells) than nulliparous females. Collectively, these data suggest that alcohol consumption during pregnancy disrupts maternal care without affecting HPA function or neurogenesis in dams. Conversely, alcohol altered HPA function in nulliparous females only, suggesting that reproductive experience buffers the long-term effects of alcohol on the HPA axis.

Prior high corticosterone exposure reduces activation of immature neurons in the ventral hippocampus in response to spatial and nonspatial memory.

Chronic stress or chronically high glucocorticoids attenuate adult hippocampal neurogenesis by reducing cell proliferation, survival, and differentiation in male rodents. Neurons are still produced in the dentate gyrus during chronically high glucocorticoids, but it is not known whether these new neurons are appropriately activated in response to spatial memory. Thus, the goal of this study was to determine whether immature granule neurons generated during chronically high glucocorticoids (resulting in a depressive-like phenotype) are differentially activated by spatial memory retrieval. Male Sprague Dawley rats received either 40 mg/kg corticosterone (CORT) or vehicle for 18 days prior to behavioral testing. Rats were tested in the forced swim test (FST) and then tested in a spatial (hippocampus-dependent) or cued (hippocampus-independent) Morris Water Maze. Tissue was then processed for doublecortin (DCX) to identify immature neurons and zif268, an immediate early gene product. As expected, CORT increased depressive-like behavior (greater immobility in the FST) however, prior CORT modestly enhanced spatial learning and memory compared with oil. Prior CORT reduced the number of DCX-expressing cells and proportion of DCX-expressing cells colabeled for zif268, but only in the ventral hippocampus. Prior CORT shifted the proportion of cells in the ventral hippocampus away from postmitotic cells and toward immature, proliferative cells, likely due to the fact that postmitotic cells were produced and matured during CORT exposure but proliferative cells were produced after high CORT exposure ceased. Compared with cue training, spatial training slightly increased DCX-expressing cells and shifted cells toward the postmitotic stage in the ventral hippocampus. These data suggest that the effects of CORT and spatial training on immature neurons are more pronounced in the ventral hippocampus. Further, high CORT reduced activation of immature neurons, suggesting that exposure to high CORT may have long-term effects on cell integration or function.

Sex differences in the HPA axis.

The hypothalamic-pituitary-adrenal (HPA) axis is a major component of the systems that respond to stress, by coordinating the neuroendocrine and autonomic responses. Tightly controlled regulation of HPA responses is critical for maintaining mental and physical health, as hyper- and hypo-activity have been linked to disease states. A long history of research has revealed sex differences in numerous components of the HPA stress system and its responses, which may partially form the basis for sex disparities in disease development. Despite this, many studies use male subjects exclusively, while fewer reports involve females or provide direct sex comparisons. The purpose of this article is to present sex comparisons in the functional and molecular aspects of the HPA axis, through various phases of activity, including basal, acute stress, and chronic stress conditions. The HPA axis in females initiates more rapidly and produces a greater output of stress hormones. This review focuses on the interactions between the gonadal hormone system and the HPA axis as the key mediators of these sex differences, whereby androgens increase and estrogens decrease HPA activity in adulthood. In addition to the effects of gonadal hormones on the adult response, morphological impacts of hormone exposure during development are also involved in mediating sex differences. Additional systems impinging on the HPA axis that contribute to sex differences include the monoamine neurotransmitters norepinephrine and serotonin. Diverse signals originating from the brain and periphery are integrated to determine the level of HPA axis activity, and these signals are, in many cases, sex-specific.

Reproductive experience does not persistently alter prefrontal cortical-dependent learning but does alter strategy use dependent on estrous phase.

Reproductive experiences in females comprise substantial hormonal and experiential changes and can exert long lasting changes in cognitive function, stress physiology, and brain plasticity. The goal of this research was to determine whether prior reproductive experience could alter a prefrontal-cortical dependent form of learning (strategy set shifting) in an operant box. In this study, female Sprague-Dawley rats were mated and mothered once or twice to produce either primiparous or biparous dams, respectively. Age-matched nulliparous controls (reproductively-naïve females with no exposure to pup cues) were also used. Maternal behaviors were also assessed to determine whether these factors would predict cognitive flexibility. For strategy set shifting, rats were trained in a visual-cue discrimination task on the first day and on the following day, were required to switch to a response strategy to obtain a reward. We also investigated a simpler form of behavioral flexibility (reversal learning) in which rats were trained to press a lever on one side of the box the first day, and on the following day, were required to press the opposite lever to obtain a reward. Estrous phase was determined daily after testing. Neither parity nor estrous phase altered total errors or trials to reach criterion in either the set-shifting or reversal-learning tasks, suggesting that PFC-dependent cognitive performance remains largely stable after 1 or 2 reproductive experiences. However, parity and estrous phase interacted to alter the frequency of particular error types, with biparous rats in estrus committing more perseverative but fewer regressive errors during the set-shifting task. This suggests that parity and estrous phase interfere with the ability to disengage from a previously used, but no longer relevant strategy. These data also suggest that parity alters the behavioral sensitivity to ovarian hormones without changing overall performance.

Endocrine substrates of cognitive and affective changes during pregnancy and postpartum.

Pregnancy and motherhood constitute periods of tremendous hormonal variation that orchestrate parturition, lactation, maternal care, maternal aggression, and recognition of offspring, among other functions. Cognitive processing also varies during pregnancy and motherhood and may serve an adaptive function in preparation for parturition and rearing. Additionally, maternal experience may have enduring consequences for the brain, behavior, and cognition long after offspring are mature. However, the early postpartum period also renders women psychologically vulnerable as approximately 15% of women experience postpartum depression, with estimates of 50-80% reporting a milder form of depression termed "maternal blues." This review will present literature on pregnancy- and parity-related changes in both cognition and affect and how these changes likely involve plastic changes within the hippocampus, a region that is sensitive to reproductive hormones. Further, this review will discuss steroid and peptide hormones that may contribute to affective and cognitive disruptions during pregnancy and postpartum. Research in this area may reveal insight into how pregnancy and motherhood alter the likelihood of developing postpartum depression and related disorders.

Short day lengths alter stress and depressive-like responses, and hippocampal morphology in Siberian hamsters.

Many psychological disorders comprise a seasonal component. For instance, seasonal affective disorder (SAD) is characterized by depression during autumn and winter. Because hippocampal atrophy may underlie the symptoms of depression and depressive-like behaviors, one goal of this study was to determine whether short days also induce structural changes in the hippocampus using photoperiod responsive rodents--Siberian hamsters. Exposure to short days increases depressive-like responses (increased immobility in the forced swim test) in hamsters. Male hamsters were housed in either short (LD 8:16) or long days (LD 16:8) for 10 weeks and tested in the forced swim test. Brains were removed and processed for Golgi impregnation. HPA axis function may account for photoperiod-related changes in depressive-like responses. Thus, stress reactivity was assessed in another cohort of photoperiod-manipulated animals. Short days reduced soma size and dendritic complexity in the CA1 region. Photoperiod did not induce gross changes in stress reactivity, but an acute stressor disrupted the typical nocturnal peak in cortisol concentrations. These data reveal that immobility induced by exposure to short days is correlated with reduced CA1 cell complexity (and perhaps connectivity). This study is the first to investigate hippocampal changes in the context of short-day induced immobility and may be relevant for understanding psychological disorders with a seasonal component.

Post-weaning environmental enrichment alters affective responses and interacts with behavioral testing to alter nNOS immunoreactivity.

Challenging early life events can dramatically affect mental health and wellbeing. Childhood trauma and neglect can increase the risk for developing depressive, anxiety, and substance abuse disorders. Early maternal separation in rodents has been extensively studied and induces long-lasting alterations in affective and stress responses. However, other developmental periods (e.g., the pubertal period) comprise a critical window whereby social and environmental complexity can exert lasting changes on the brain and behavior. In this study, we tested whether early life environmental complexity impacts affective responses, aggressive behaviors, and expression of neuronal nitric oxide synthase (nNOS), the synthetic enzyme for nitric oxide, in adulthood. Mice were weaned into social+nonsocial enrichment, social only enrichment, or standard (isolated) laboratory environments and were tested in open field, elevated plus maze, forced swim, and resident-intruder aggression tests 60 days later. Social+nonsocial enrichment reduced locomotor behavior and anxiety-like responses in the open field and reduced depressive-like responses in the forced swim test. Social housing increased open arm exploration in the elevated plus maze. Both social+nonsocial enrichment and social housing only reduced aggressive behaviors compared with isolation. Social+nonsocial enrichment also increased body mass gain throughout the study. Finally, socially-housed mice had reduced corticosterone concentrations compared with social+nonsocial-enriched mice. Behavioral testing reduced nNOS-positive neurons in the basolateral amygdala and the ventral lateral septum, but not in the social+nonsocial-enriched mice, suggesting that environmental complexity may buffer the brain against some environmental perturbations.

Dietary arginine depletion reduces depressive-like responses in male, but not female, mice.

Previous behavioral studies have manipulated nitric oxide (NO) production either by pharmacological inhibition of its synthetic enzyme, nitric oxide synthase (NOS), or by deletion of the genes that code for NOS. However manipulation of dietary intake of the NO precursor, L-arginine, has been understudied in regard to behavioral regulation. L-Arginine is a common amino acid present in many mammalian diets and is essential during development. In the brain L-arginine is converted into NO and citrulline by the enzyme, neuronal NOS (nNOS). In Experiment 1, paired mice were fed a diet comprised either of an L-arginine-depleted, L-arginine-supplemented, or standard level of L-arginine during pregnancy. Offspring were continuously fed the same diets and were tested in adulthood in elevated plus maze, forced swim, and resident-intruder aggression tests. L-Arginine depletion reduced depressive-like responses in male, but not female, mice and failed to significantly alter anxiety-like or aggressive behaviors. Arginine depletion throughout life reduced body mass overall and eliminated the sex difference in body mass. Additionally, arginine depletion significantly increased corticosterone concentrations, which negatively correlated with time spent floating. In Experiment 2, adult mice were fed arginine-defined diets two weeks prior to and during behavioral testing, and again tested in the aforementioned tests. Arginine depletion reduced depressive-like responses in the forced swim test, but did not alter behavior in the elevated plus maze or the resident intruder aggression test. Corticosterone concentrations were not altered by arginine diet manipulation in adulthood. These results indicate that arginine depletion throughout development, as well as during a discrete period during adulthood ameliorates depressive-like responses. These results may yield new insights into the etiology and sex differences of depression.

Short photoperiods alter cannabinoid receptor expression in hypothalamic nuclei related to energy balance.

This study examined the photoperiodic regulation of energy balance and cannabinoid receptor expression in the Siberian hamster (Phodopus sungorus) hypothalamus. Short day lengths, beginning at weaning, reduced food intake, body mass and fat pad masses and also decreased cannabinoid receptor immunostaining in the anterior and lateral hypothalamic nuclei of male hamsters. These data suggest a potential role for reduced cannabinoid drive in mediating short day-induced alterations in energy balance.

Potential animal models of seasonal affective disorder.

Seasonal affective disorder (SAD) is characterized by depressive episodes during winter that are alleviated during summer and by morning bright light treatment. Currently, there is no animal model of SAD. However, it may be possible to use rodents that respond to day length (photoperiod) to understand how photoperiod can shape the brain and behavior in humans. As nights lengthen in the autumn, the duration of the nightly elevation of melatonin increase; seasonally breeding animals use this information to orchestrate seasonal changes in physiology and behavior. SAD may originate from the extended duration of nightly melatonin secretion during fall and winter. These similarities between humans and rodents in melatonin secretion allows for comparisons with rodents that express more depressive-like responses when exposed to short day lengths. For instance, Siberian hamsters, fat sand rats, Nile grass rats, and Wistar rats display a depressive-like phenotype when exposed to short days. Current research in depression and animal models of depression suggests that hippocampal plasticity may underlie the symptoms of depression and depressive-like behaviors, respectively. It is also possible that day length induces structural changes in human brains. Many seasonally breeding rodents undergo changes in whole brain and hippocampal volume in short days. Based on strict validity criteria, there is no animal model of SAD, but rodents that respond to reduced day lengths may be useful to approximate the neurobiological phenomena that occur in people with SAD, leading to greater understanding of the etiology of the disorder as well as novel therapeutic interventions.

Light at night increases body mass by shifting the time of food intake.

The global increase in the prevalence of obesity and metabolic disorders coincides with the increase of exposure to light at night (LAN) and shift work. Circadian regulation of energy homeostasis is controlled by an endogenous biological clock that is synchronized by light information. To promote optimal adaptive functioning, the circadian clock prepares individuals for predictable events such as food availability and sleep, and disruption of clock function causes circadian and metabolic disturbances. To determine whether a causal relationship exists between nighttime light exposure and obesity, we examined the effects of LAN on body mass in male mice. Mice housed in either bright (LL) or dim (DM) LAN have significantly increased body mass and reduced glucose tolerance compared with mice in a standard (LD) light/dark cycle, despite equivalent levels of caloric intake and total daily activity output. Furthermore, the timing of food consumption by DM and LL mice differs from that in LD mice. Nocturnal rodents typically eat substantially more food at night; however, DM mice consume 55.5% of their food during the light phase, as compared with 36.5% in LD mice. Restricting food consumption to the active phase in DM mice prevents body mass gain. These results suggest that low levels of light at night disrupt the timing of food intake and other metabolic signals, leading to excess weight gain. These data are relevant to the coincidence between increasing use of light at night and obesity in humans.