Microglia contribute to mammary tumor-induced neuroinflammation in a female mouse model.

Following diagnosis but before treatment, up to 30% of breast cancer patients report behavioral side effects (e.g., anxiety, depression, memory impairment). Our rodent mammary tumor model recapitulates aspects of these behavioral sequelae, as well as elevated circulating and brain inflammatory mediators. Neuroinflammation is a proposed mechanism underlying the etiology of mood disorders and cognitive deficits, and therefore may be contributing to tumor-associated behavioral side effects. The cellular mechanisms by which tumor-induced neuroinflammation occurs remain unknown, making targeted treatment approaches inaccessible. Here, we tested the hypotheses that microglia are the primary cells driving tumor-induced neuroinflammation and behavioral side effects. Young adult female BALB/c mice were induced with a 67NR mammary tumor; tumor-free controls underwent a sham surgery. Mammary tumors increased IBA1+ and GFAP+ staining in the amygdala and hippocampus relative to tumor-free controls. However, tumors did not alter gene expression of Percoll-enriched microglia isolated from the whole brain. While cognitive, social, and anhedonia-like behaviors were not altered in tumor-bearing mice, tumors increased central tendency in the open-field test; microglia depletion did not reverse this effect. Brain region RT-qPCR data indicated that microglia depletion attenuated tumor-induced elevations of neuroinflammatory gene expression in a region- and mediator-specific manner. These results indicate a causal role of microglia in tumor-induced neuroinflammation. This research advances our understanding of the cellular mechanisms underlying tumor-induced neuroinflammation in order to understand how brain responses (e.g., behavior) may be altered with subsequent cancer-related immune challenges.

Paternal deprivation induces vigilance-avoidant behavior and accompanies sex-specific alterations in stress reactivity and central proinflammatory cytokine response in California mice (Peromyscus californicus).

RATIONALE: Early-life stress (ELS) can increase anxiety, reduce prosocial behaviors, and impair brain regions that facilitate emotional and social development. This knowledge greatly stems from assessing disrupted mother-child relationships, while studies investigating the long-term effects of father-child relationships on behavioral development in children are scarce. However, available evidence suggests that fathers may uniquely influence a child's behavioral development in a sex-specific manner. Rodent models examining mother-offspring interaction demonstrate relationships among ELS, neuroinflammatory mediators, and behavioral development; yet, the role paternal care may play in neuroimmune functioning remains unreported. OBJECTIVES: Using the biparental California mouse (Peromyscus californicus), we examined to what extent paternal deprivation impairs social and anxiety-like behaviors, augments peripheral corticosterone (CORT) response, and alters central proinflammatory cytokine production following an acute stressor in adulthood. METHODS: Biparentally reared and paternally deprived (permanent removal of the sire 24 h post-birth) adult mice were assessed for sociability, preference for social novelty, social vigilance, and social avoidance behaviors, followed by novelty-suppressed feeding (NSF) testing for general anxiety-like behavior. Following an acute stressor, circulating CORT concentrations and region-specific proinflammatory cytokine concentrations were determined via radioimmunoassay and Luminex multianalyte analysis, respectively. RESULTS: In response to a novel same-sex conspecific, social vigilance behavior was associated with reduced sociability and increased avoidance in paternally deprived mice-an effect not observed in biparentally reared counterparts. Yet, in response to a familiar same-sex conspecific, social vigilance persisted but only in paternally deprived females. The latency to consume during NSF testing was not significantly altered by paternal deprivation. In response to an acute physical stressor, lower circulating CORT concentrations were observed in paternally deprived females. Compared to control-reared males, paternal deprivation increased hypothalamic interleukin-1ß, but decreased hippocampal IL-6 protein concentration. CONCLUSION: Greater social vigilance behavior was demonstrated in paternally deprived mice while they avoided social interaction with a novel same-sex conspecific; however, in response to a familiar same-sex conspecific, paternal deprivation increased social vigilance behavior but only in females. It is possible that different neurobiological mechanisms underlie these observed behavioral outcomes as sex-specific central proinflammatory cytokine and stress responsivity were observed in paternally deprived offspring.

A sex difference in mouse dopaminergic projections from the midbrain to basolateral amygdala.

BACKGROUND: Dopaminergic circuits play important roles in the motivational control of behavior and dysfunction in dopaminergic circuits have been implicated in several psychiatric disorders, such as schizophrenia and depression. While these disorders exhibit different incidence rates in men and women, the potential sex differences in the underlying neural circuits are not well-understood. Previous anatomical tracing studies in mammalian species have revealed a prominent circuit projection connecting the dopaminergic midbrain ventral tegmental area (VTA) to the basolateral amygdala (BLA), which is involved in emotional processing and associative learning. However, whether there is any sex difference in this anatomical circuit remains unknown. METHODS: To study the potential sex differences in the VTA-to-BLA dopaminergic circuit, we injected two viral vectors encoding fluorescent reporters of axons and synaptic boutons (AAV-FLEX-tdTomato and AAV-FLEX-SynaptophysinGFP, respectively) into the VTA of a mouse transgenic driver line (tyrosine hydroxylase promoter-driven Cre, or TH-Cre), which restricts the reporter expression to dopaminergic neurons. We then used confocal fluorescent microscopy to image the distribution and density of dopaminergic axons and synaptic boutons in serial sections of both male and female mouse brain. RESULTS: We found that the overall labeling intensity of VTA-to-BLA dopaminergic projections is intermediate among forebrain dopaminergic pathways, significantly higher than the projections to the prefrontal cortex, but lower than the projections to the nucleus accumbens. Within the amygdala areas, dopaminergic axons are concentrated in BLA. Although the size of BLA and the density of dopaminergic axons within BLA are similar between male and female mice, the density of dopaminergic synaptic boutons in BLA is significantly higher in male brain than female brain. CONCLUSIONS: Our results demonstrate an anatomical sex difference in mouse dopaminergic innervations from the VTA to BLA. This finding may provide a structural foundation to study neural circuit mechanisms underlying sex differences in motivational and emotional behaviors and related psychiatric dysfunctions.

Sex-specific effects of neonatal paternal deprivation on microglial cell density in adult California mouse (Peromyscus californicus) dentate gyrus.

Adverse early-life experiences are risk factors for psychiatric disease development, resulting in stress-related neuronal modeling and neurobehavioral changes. Stressful experiences modulate the immune system, contributing to neuronal damage in higher cortical regions, like the hippocampus. Moreover, early-life stressors dysregulate the function of microglia, the resident immune cells of the brain, in the developing hippocampus. Paternal deprivation, an early-life stressor in many biparental species, facilitates sex-dependent inhibitions in hippocampal plasticity, but parental contributors to these sex-specific outcomes are unknown. Also, neurobiological mechanisms contributing to impairments in hippocampal neuroplasticity are less known. Thus, our goals were to 1) determine whether parental behavior is altered in maternal females following removal of the paternal male, 2) assess the effects of paternal deprivation on dentate gyrus (DG) volume and microglia proliferation, and 3) determine if early-life experimental handling mitigates sex-specific reductions in DG cell survival. California mice were born to multiparous breeders and reared by both parents (biparental care) or by their mother alone (i.e., father removed on postnatal day 1; paternal deprivation). One cohort of offspring underwent offspring retrieval tests for eight days beginning on postnatal day 2. On PND 68, these offspring (and a second cohort of mice without behavioral testing) were euthanized and brains visualized for bromodeoxyuridine (BrdU) and neuron-specific class III beta-tubulin (TuJ-1) or ionized calcium binding adaptor molecule 1 (Iba1). While mate absence did not impair maternal retrieval, paternal deprivation reduced DG volume, but Iba1+ cell density was only higher in paternally-deprived females. Neither sex or paternal deprivation significantly altered the number of BrdU+ or Tuj1+ cells in the DG - an absence of a reduction in cell survival may be related to daily handing during early offspring retrieval tests. Together, these data suggest that paternal deprivation impairs hippocampal plasticity; however, sex and early environment may influence the magnitude of these outcomes.

Comparative anatomical analysis of dopamine systems in Mus musculus and Peromyscus californicus.

Dopamine plays important roles in motivational and social behaviors in mammals, and it has been implicated in several human neurological and psychiatric disorders. Rodents are used extensively as experimental models to study dopamine function in health and disease. However, interspecies differences of dopamine systems remain incompletely characterized. Here, we assessed whether the commonly referenced anatomical organization of dopamine systems in Mus musculus differs from another rodent species, Peromyscus californicus, which exhibits unique social behaviors such as biparental care. We applied tyrosine hydroxylase immunofluorescence labeling and high-throughput microscopy to establish whole-brain maps of dopamine systems in P. californicus. By comparing these maps to those from M. musculus, we identified unexpected anatomical similarity and difference between these two species. A sex difference in dopamine neurons at the anteroventral periventricular nucleus of hypothalamus, which has been implicated in regulating the maternal behaviors of the uniparental M. musculus, is similarly present in the biparental P. californicus. In contrast, major interspecies differences from M. musculus are found in the ventral midbrain and striatum of P. californicus, including the expansion of midbrain dopamine neurons into the ventral substantia nigra and the presence of an internal capsule-like white matter tract that demarcates a dorsomedial area from the rest of the striatum. These features identified in P. californicus resemble the anatomical organization of the primate brain more closely compared to those in M. musculus. Our findings suggest that P. californicus is a unique model organism for studying the evolution of dopamine systems in mammals and the disorders of dopamine systems.

Cortisol Reactivity and Observed Parenting among Mothers of Children with and without ADHD.

OBJECTIVE: Neurobiological models suggest links between maternal cortisol reactivity and parenting; however, no studies have examined cortisol reactivity and parenting in mothers of school-age children with ADHD. METHOD: We examined the relationship between observed parenting and maternal cortisol reactivity in two laboratory contexts: the Trier Social Stress Task (TSST) and parenting-child interaction (PCI). Mothers of children with (N = 24) and without (N = 36) ADHD participated. RESULTS: During the TSST, greater cortisol output and increase were associated with decreased positive and increased negative parenting. However, during the PCI, cortisol output was associated with increased self-reported and observed positive parenting, and decreased observed negative parenting. Cortisol change during the PCI was associated with decreased observed positive parenting and increased self-reported negative parenting. Among mothers of children with ADHD, cortisol output during the PCI was negatively associated with negative, inconsistent parenting. Change in cortisol predicted more inconsistent discipline and corporal punishment. CONCLUSION: Findings contribute to an integrative biological, psychological, and cognitive process model of parenting in families of children with ADHD.

Hormones and neuroplasticity: A lifetime of adaptive responses.

Major life transitions often co-occur with significant fluctuations in hormones that modulate the central nervous system. These hormones enact neuroplastic mechanisms that prepare an organism to respond to novel environmental conditions and/or previously unencountered cognitive, emotional, and/or behavioral demands. In this review, we will explore several examples of how hormones mediate neuroplastic changes in order to produce adaptive responses, particularly during transitions in life stages. First, we will explore hormonal influences on social recognition in both males and females as they transition to sexual maturity. Next, we will probe the role of hormones in mediating the transitions to motherhood and fatherhood, respectively. Finally, we will survey the long-term impact of reproductive experience on neuroplasticity in females, including potential protective effects and risk factors associated with reproductive experience in mid-life and beyond. Ultimately, a more complete understanding of how hormones influence neuroplasticity throughout the lifespan, beyond development, is necessary for understanding how individuals respond to life changes in adaptive ways.

Acute forced exercise increases Bdnf IV mRNA and reduces exploratory behavior in C57BL/6J mice.

Acute exercise has been shown to improve memory in humans. Potential mechanisms include increased Bdnf expression, noradrenergic activity and modification of glutamate receptors. Because mice are commonly used to study exercise and brain plasticity, it is important to explore how acute exercise impacts behavior in this model. C57BL/6J mice were assigned to three groups: control, moderate-intensity running, and high-intensity running. Control mice were placed on a stationary treadmill for 30 minutes and moderate- and high-intensity mice ran for 30 minutes at 12 and 15-17 m/min, respectively. Mice were sacrificed immediately after running and the hippocampus removed. Total Bdnf, Bdnf exon IV, and glutamate receptor subunits were quantified with quantitative polymerase chain reaction. Total and phosphorylated GluR1 (Ser845 and Ser831) protein was quantified following immunoblotting. Utilizing the same protocol for control and high-intensity running, object location memory was examined in a separate cohort of mice. Anxiety-like behavior was assessed in the open field task (OFT) in a third cohort of mice that were separated into four groups: control-saline, control-DSP-4, acute exercise-saline, and acute exercise-DSP-4. DSP-4 was used to lesion the central noradrenergic system. We observed higher Bdnf IV mRNA in high-intensity runners compared to controls, but no effects of acute exercise on memory. In the OFT, runners traveled less distance and spent more time grooming than controls. DSP-4 did not attenuate the effects of exercise. A single bout of exercise increases Bdnf IV mRNA in an intensity-dependent manner; however, high-intensity running reduces exploratory behavior in C57BL/6J mice.

Sexual activity modulates neuroinflammatory responses in male rats.

Immune activity influences reproduction, however, the extent to which mating experience may inversely alter immune pathways is poorly understood. A few studies in humans suggest that mating triggers a circulating immune and hypothalamic-pituitary-adrenal axis response. In male rats, mating experience enhances neuroplasticity and improves cognitive function and affective-like behavior, independent of the physical activity component. Yet, the extent to which mating experience may influence immune responses in the brain remain unexplored. Here, we hypothesized that recent mating experience in male rats increases neuroinflammatory signaling (via lipopolysaccharide [LPS] stimulation, i.p.) and associated sickness behaviors (i.e., food intake, weight loss) relative to sexually-naïve controls. Virgin male rats were exposed to a sexually non-receptive (control) or sexually-receptive female for 30 min for six consecutive days. Immediately following the last mating experience, rats were administered a saline or LPS injection and euthanized four hours later. Mating increased Tnfα responses to LPS in the brain, which positively correlated with LPS-induced weight loss. Mating also increased peripheral corticosterone among saline-treated rats, but this corticosterone response was attenuated in the most proficient copulators (e.g., shortest latencies). Thus, recent mating experience may be a unique modulator of select stimulated inflammatory signals that are relevant to adaptive neuroimmune responses and behavior.

Measuring corticosterone concentrations over a physiological dynamic range in female rats.

Accurate assessment of plasma corticosterone, the primary stress hormone in rodents, is an essential part of characterizing the stress response in experimental animals. To this end, both enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) remain widely used. However, considerable assay-specific variability exists among commercially available corticosterone assays due to differing assay principles, detection methods, range, and sensitivity. While technical comparisons of commercially available corticosterone assays have previously been conducted, the ability to detect acute stress-induced endocrine changes has not been compared among these methods to date. Using the forced swim test, a commonly utilized behavioral paradigm in rodents as a physiologically-relevant acute stress challenge, we compared four commercial corticosterone assays - three ELISA kits and one RIA kit - in their ability to detect corticosterone across a dynamic range of both baseline and acute swim stress-driven concentrations. While all methods yielded results that were consistent at measuring relative differences between samples, only two of the four assays evaluated detected a statistically significant increase in corticosterone in rats exposed to acute swim stress compared to rats at baseline. The ELISA kit from Enzo Life Sciences demonstrated the greatest percent increase in plasma corticosterone from baseline to acute stress conditions. The RIA kit from MP Biomedicals also detected a significant corticosterone increase and yielded higher concentrations of corticosterone both at baseline and in the acute stress condition relative to the other three assays. We conclude that choice of assay can impact interpretation of data due to differences in efficacy across a dynamic range of physiological concentrations of corticosterone.

Enduring Effects of Paternal Deprivation in California Mice (Peromyscus californicus): Behavioral Dysfunction and Sex-Dependent Alterations in Hippocampal New Cell Survival.

Early-life experiences with caregivers can significantly affect offspring development in human and non-human animals. While much of our knowledge of parent-offspring relationships stem from mother-offspring interactions, increasing evidence suggests interactions with the father are equally as important and can prevent social, behavioral, and neurological impairments that may appear early in life and have enduring consequences in adulthood. In the present study, we utilized the monogamous and biparental California mouse (Peromyscus californicus). California mouse fathers provide extensive offspring care and are essential for offspring survival. Non-sibling virgin male and female mice were randomly assigned to one of two experimental groups following the birth of their first litter: (1) biparental care: mate pairs remained with their offspring until weaning; or (2) paternal deprivation (PD): paternal males were permanently removed from their home cage on postnatal day (PND) 1. We assessed neonatal mortality rates, body weight, survival of adult born cells in the dentate gyrus of the hippocampus, and anxiety-like and passive stress-coping behaviors in male and female young adult offspring. While all biparentally-reared mice survived to weaning, PD resulted in a ~35% reduction in survival of offspring. Despite this reduction in survival to weaning, biparentally-reared and PD mice did not differ in body weight at weaning or into young adulthood. A sex-dependent effect of PD was observed on new cell survival in the dentate gyrus of the hippocampus, such that PD reduced cell survival in female, but not male, mice. While PD did not alter classic measures of anxiety-like behavior during the elevated plus maze task, exploratory behavior was reduced in PD mice. This observation was irrespective of sex. Additionally, PD increased some passive stress-coping behaviors (i.e., percent time spent immobile) during the forced swim task-an effect that was also not sex-dependent. Together, these findings demonstrate that, in a species where paternal care is not only important for offspring survival, PD can also contribute to altered structural and functional neuroplasticity of the hippocampus. The mechanisms contributing to the observed sex-dependent alterations in new cell survival in the dentate gyrus should be further investigated.

Estrogen-dependent modifications to hippocampal plasticity in paternal California mice (Peromyscus californicus).

In many biparental species, mothers and fathers experience similar modifications to circulating hormones. With these modifications come alterations in neural structure and function suggesting that neuroendocrine mechanisms may underlie postpartum plasticity in both males and females. In the biparental California mouse (Peromyscus californicus), adult neurogenesis is maintained and anxiety-like behavior is attenuated in fathers during the mid-postpartum period. Given a causal relationship between estrogen and regulation of both adult neurogenesis and anxiety, we aimed to elucidate the role of estrogen-dependent mechanisms in paternal experience-related modifications to hippocampal neuroplasticity in California mice. In Experiment 1, hippocampal estrogen receptor beta (ERß) mRNA expression, along with circulating estradiol concentrations, were determined throughout the postpartum period. An upregulation in ERß expression was observed in postnatal day 16 males compared to virgins. Additionally, a rise in circulating estradiol concentrations was detected on postnatal day 2 compared to virgins; levels began to decline toward virgin levels on postnatal day 16 and postnatal day 30. In Experiment 2, we determined the role of estrogen-dependent mechanisms in adult neurogenesis and anxiety-like behavior by treating virgin and paternal males with saline or the selective estrogen receptor modulator, tamoxifen (TMX), during the time of axon extension (i.e., one week after bromodeoxyuridine injection). While TMX failed to alter elevated plus maze performance, TMX treatment inhibited survival of adult born neurons but only in paternal mice. These findings highlight the potential for estrogen-dependent pathways to mediate hippocampal adult neurogenesis in paternal mice.

Separation increases passive stress-coping behaviors during forced swim and alters hippocampal dendritic morphology in California mice.

Individuals within monogamous species form bonds that may buffer against the negative effects of stress on physiology and behavior. In some species, involuntary termination of the mother-offspring bond results in increased symptoms of negative affect in the mother, suggesting that the parent-offspring bond may be equally as important as the pair bond. To our knowledge, the extent to which affect in paternal rodents is altered by involuntary termination of the father-offspring bond is currently unknown. Here, we investigated to what extent separation and paternal experience alters passive stress-coping behaviors and dendritic morphology in hippocampal subfields of California mice (Peromyscus californicus). Irrespective of paternal experience, separated mice displayed shorter latencies to the first bout of immobility, longer durations of immobility, and more bouts of immobility than control (non-separated) mice. This effect of separation was exacerbated by paternal experience in some measures of behavioral despair-separation from offspring further decreased the latency to immobility and increased bouts of immobility. In the dentate gyrus, separation reduced dendritic spine density regardless of paternal experience. Increased spine density was observed on CA1 basal, but not apical, dendrites following paternal experience. Regardless of offspring presence, fatherhood was associated with reduced apical dendritic spine density in area CA3 of the hippocampus. Separation enhanced complexity of both basal and apical dendrites in CA1, while fatherhood reduced dendritic complexity in this region. Our data suggest that forced dissolution of the pair bond induces passive stress-coping behaviors and contributes to region-specific alterations in hippocampal structure in California mouse males.

Fatherhood contributes to increased hippocampal spine density and anxiety regulation in California mice.

INTRODUCTION: Parenting alters the hippocampus, an area of the brain that undergoes significant experience-induced plasticity and contributes to emotional regulation. While the relationship between maternal care and hippocampal neuroplasticity has been characterized, the extent to which fatherhood alters the structure and function of the hippocampus is far less understood. METHODS: Here, we investigated to what extent fatherhood altered anxiety regulation and dendritic morphology of the hippocampus using the highly paternal California mouse (Peromyscus californicus). RESULTS: Fathers spent significantly more time on the open arms of the elevated plus maze, compared to non-fathers. Total distance traveled in the EPM was not changed by paternal experience, which suggests that the increased time spent on the open arms of the maze indicates decreased anxiety-like behavior. Fatherhood also increased dendritic spine density of granule cells in the dentate gyrus and basal dendrites of pyramidal cells in area CA1 of the hippocampus. CONCLUSIONS: These findings parallel those observed in maternal rodents, suggesting that the hippocampus of fathers and mothers respond similarly to offspring.

Sexual experience enhances cognitive flexibility and dendritic spine density in the medial prefrontal cortex.

The medial prefrontal cortex is important for cognitive flexibility, a capability that is affected by environmental conditions and specific experiences. Aversive experience, such as chronic restraint stress, is known to impair performance on a task of cognitive flexibility, specifically attentional set-shifting, in rats. Concomitant with this performance decrement, chronic stress reduces the number of dendritic spines on pyramidal neurons in the medial prefrontal cortex. No previous studies have examined whether a rewarding experience, namely mating, affects cognitive flexibility and dendritic spines in the medial prefrontal cortex of male rats. To test this possibility, we exposed adult male rats to sexual receptive females once daily for one week, assessed attentional set-shifting performance, and then analyzed their brains for changes in dendritic spines. We found that sexual experience improved performance on extradimensional set-shifting, which is known to require the medial prefrontal cortex. Additionally, we observed increased dendritic spine density on apical and basal dendrites of pyramidal neurons in the medial prefrontal cortex, but not the orbitofrontal cortex, after sexual experience. We also found that sexual experience enhanced dendritic spine density on granule neurons of the dentate gyrus. The ventral hippocampus sends a direct projection to the medial prefrontal cortex, raising the possibility that experience-dependent changes in the hippocampus are necessary for alterations in medial prefrontal cortex structure and function. As a first attempt at investigating this, we inactivated the ventral hippocampus with the GABA agonist muscimol, after each daily bout of sexual experience to observe whether the beneficial effects on cognitive flexibility were abolished. Contrary to our hypothesis, blocking hippocampal activity after sexual experience had no impact on enhanced cognitive flexibility. Taken together, these findings indicate that sexual experience enhances medial prefrontal cortex dendritic spine density and cognitive flexibility but that these effects may not require continual input from the hippocampus.

Meloxicam blocks neuroinflammation, but not depressive-like behaviors, in HIV-1 transgenic female rats.

Adolescents living with human immunodeficiency virus (HIV) comprise approximately 12% of the HIV-positive population worldwide. HIV-positive adolescents experience a higher rate of clinical depression, a greater risk of sexual and drug abuse behaviors, and a decreased adherence to highly active antiretroviral therapies (HAART). Using adolescent HIV-1 transgenic rats (HIV-1 tg) that display related immune response alterations and pathologies, this study tested the hypothesis that developmental expression of HIV-1-related proteins induces a depressive-like phenotype that parallels a decrease in hippocampal cell proliferation and an increase in pro-inflammatory cytokine expression in the hippocampus. Consistent with this hypothesis, adolescent HIV-1 tg rats demonstrated a depressive-like behavioral phenotype, had decreased levels of cell proliferation, and exhibited elevated expression of monocyte chemotactic protein-1 (Mcp-1) in the hippocampus relative to controls. Subsequently, we tested the ability of meloxicam, a selective COX-2 inhibitor, to attenuate behavioral deficits via inflammatory mechanisms. Daily meloxicam treatments did not alter the behavioral profile despite effectively reducing hippocampal inflammatory gene expression. Together, these data support a biological basis for the co-morbid manifestation of depression in HIV-positive patients as early as in adolescence and suggest that modifications in behavior manifest independent of inflammatory activity in the hippocampus.

SSRI or CRF antagonism partially ameliorate depressive-like behavior after adolescent social defeat.

Depression and anxiety during adolescence are complex disorders due to persistent effects on physiology and behavior. Selective-serotonin reuptake inhibitors (SSRI) are currently the most widely used pharmacological intervention for depression. Corticotropin-releasing factor one (CRF1) receptor antagonists represent a novel class of compounds that may have efficacy for depressive and anxiety disorders. This study used an animal model of chronic adolescent stress to determine the efficacy of the SSRI fluoxetine, and a novel CRF1 receptor antagonist, GSK876008, on prevention of the behavioral effects of chronic adolescent stress. Male rats were exposed to chronic social defeat stress, fluoxetine, and/or GSK876008 from postnatal day 28-50. Chronic stress-induced depressive-like behaviors were partially attenuated by either concurrent fluoxetine or GSK876008. Fluoxetine blunted body mass gain in the adolescents exposed to chronic stress. The collective data demonstrate similar efficacy between a SSRI and a CRF1 receptor antagonist in the attenuation of stress-induced anhedonia but fewer side effects were observed in those rats treated with the CRF1 receptor antagonist. These data suggest that CRF1 receptor antagonists may be a viable alternative for treatment of depressive behaviors in adolescents.

Sexual experience restores age-related decline in adult neurogenesis and hippocampal function.

Aging is associated with compromised hippocampal function and reduced adult neurogenesis in the dentate gyrus. As new neurons have been linked to hippocampal functions, such as cognition, age-related decline in new neuron formation may contribute to impaired hippocampal function. We investigated whether a rewarding experience known to stimulate neurogenesis in young adult rats, namely sexual experience, would restore new neuron production and hippocampal function in middle-aged rats. Sexual experience enhanced the number of newly generated neurons in the dentate gyrus with both single and repeated exposures in middle-aged rats. Following continuous long-term exposure to sexual experience, cognitive function was improved. However, when a prolonged withdrawal period was introduced between the final mating experience and behavioral testing, the improvements in cognitive function were lost despite the presence of more new neurons. Taken together, these results suggest that repeated sexual experience can stimulate adult neurogenesis and restore cognitive function in the middle-aged rat as long as the experience persists throughout the testing period. The extent to which changes in adult neurogenesis underlie those in cognition remain unknown.

Adult neurogenesis: optimizing hippocampal function to suit the environment.

Numerous studies have attempted to determine the function of adult neurogenesis in the hippocampus using methods to deplete new neurons and examine changes in behaviors associated with this brain region. This approach has produced a set of findings that, although not entirely consistent, suggest new neurons are associated with improved learning and reduced anxiety. This paper attempts to synthesize some of these findings into a model that proposes adaptive significance to experience-dependent alterations in new neuron formation. We suggest that the modulation of adult neurogenesis, as well as of the microcircuitry associated with new neurons, by experience prepares the hippocampus to meet the specific demands of an environment that is predictably similar to one that existed previously. Reduced neurogenesis that occurs with persistent exposure to a high threat environment produces a hippocampus that is more likely to respond with behavior that maximizes the chance of survival. Conversely, enhanced neurogenesis that occurs with continual exposure to a rewarding environment leads to behavior that optimizes the chances of successful reproduction. The persistence of this form of plasticity throughout adulthood may provide the neural substrate for adaptive responding to both stable and dynamic environmental conditions.