Effects of social defeat stress and fluoxetine treatment on neurogenesis and behavior in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc.

Depression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behavior and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress-induced behavioral symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression-like effects, including social avoidance and anxiety-like behavior. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety-like behavior. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioral benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.

Neurog2 and Ascl1 together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex.

A derepression mode of cell-fate specification involving the transcriptional repressors Tbr1, Fezf2, Satb2, and Ctip2 operates in neocortical projection neurons to specify six layer identities in sequence. Less well understood is how laminar fate transitions are regulated in cortical progenitors. The proneural genes Neurog2 and Ascl1 cooperate in progenitors to control the temporal switch from neurogenesis to gliogenesis. Here we asked whether these proneural genes also regulate laminar fate transitions. Several defects were observed in the derepression circuit in Neurog2-/-;Ascl1-/- mutants: an inability to repress expression of Tbr1 (a deep layer VI marker) during upper-layer neurogenesis, a loss of Fezf2+/Ctip2+ layer V neurons, and precocious differentiation of normally late-born, Satb2+ layer II-IV neurons. Conversely, in stable gain-of-function transgenics, Neurog2 promoted differentiative divisions and extended the period of Tbr1+/Ctip2+ deep-layer neurogenesis while reducing Satb2+ upper-layer neurogenesis. Similarly, acute misexpression of Neurog2 in early cortical progenitors promoted Tbr1 expression, whereas both Neurog2 and Ascl1 induced Ctip2. However, Neurog2 was unable to influence the derepression circuit when misexpressed in late cortical progenitors, and Ascl1 repressed only Satb2. Nevertheless, neurons derived from late misexpression of Neurog2 and, to a lesser extent, Ascl1, extended aberrant subcortical axon projections characteristic of early-born neurons. Finally, Neurog2 and Ascl1 altered the expression of Ikaros and Foxg1, known temporal regulators. Proneural genes thus act in a context-dependent fashion as early determinants, promoting deep-layer neurogenesis in early cortical progenitors via input into the derepression circuit while also influencing other temporal regulators.

Mice lacking the transcription factor SHOX2 display impaired cerebellar development and deficits in motor coordination.

Purkinje cells of the developing cerebellum secrete the morphogen sonic hedgehog (SHH), which is required to maintain the proliferative state of granule cell precursors (GCPs) prior to their differentiation and migration to form the internal granule layer (IGL). Despite a wealth of knowledge regarding the function of SHH during cerebellar development, the upstream regulators of Shh expression during this process remain largely unknown. Here we report that the murine short stature homeobox 2 (Shox2) gene is required for normal Shh expression in dorsal-residing Purkinje cells. Using two different Cre drivers, we show that elimination of Shox2 in the brain results in developmental defects in the inferior colliculus and cerebellum. Specifically, loss of Shox2 in the cerebellum results in precocious differentiation and migration of GCPs from the external granule layer (EGL) to the IGL. This correlates with premature bone morphogenetic protein 4 (Bmp4) expression in granule cells of the dorsal cerebellum. The size of the neonatal cerebellum is reduced in Shox2-mutant animals, which is consistent with a reduction in the number of GCPs present in the EGL, and could account for the smaller vermis and thinner IGL present in adult Shox2mutants. Shox2-mutant mice also display reduced exploratory activity, altered gait and impaired motor coordination. Our findings are the first to show a role for Shox2 in brain development. We provide evidence that Shox2 plays an important role during cerebellar development, perhaps to maintain the proper balance of Shh and Bmp expression levels in the dorsal vermis, and demonstrate that in the absence of Shox2, mice display both cerebellar impairments and deficits in motor coordination, ultimately highlighting the importance of Shox2 in the cerebellum.

Predictors of caregiver depression and family functioning after perinatal stroke.

BACKGROUND: Perinatal stroke is a leading cause of cerebral palsy and lifelong neurological morbidity. Studies on perinatal stroke outcomes are increasing, although examinations of its broader impact on parents and families have been limited. A recent study found that parents of children with moderate and severe outcomes have increased risk for psychosocial concerns, including depressive symptoms and poor family functioning. Other parents adapt remarkably well, but how this occurs is unknown. The primary aim of this study was to examine predictors of parent and family outcomes, namely caregiver depression and family functioning. The secondary aim was to explore potential mediators and moderators of the relationship between condition severity and parent and family outcomes. METHODS: Parents were recruited from a large, population-based perinatal stroke research cohort, and they completed measures assessing their demographics, social supports, stress levels, marital quality, feelings of guilt and blame, psychological well-being, and family functioning. Bivariate analyses compared these variables. Predictor variables, mediators, and moderators were chosen according to the strength of their relationship with the outcome variables (i.e., caregiver depression and family functioning) and theory. Hierarchical regression, mediator, and moderator analyses were conducted accordingly. RESULTS: A total of 103 parents participated in this study (76 mothers, 27 fathers; mean age of 39.2 years; mean child age of 7.46 years). Condition severity, anxiety, social support, and blame independently predicted caregiver depression while condition severity, stress levels, and marital quality independently predicted family functioning. Blame regarding the cause of their child's condition also mediated the relationship between condition severity and caregiver depression. CONCLUSIONS: Adverse parental outcomes can be predicted in perinatal stroke populations. Moreover, anxiety and stress management techniques, marital support, and psychoeducation regarding the unpreventable nature of perinatal stroke may be utilized in the future to enhance family outcomes.

Increased aggression, improved spatial memory, and reduced anxiety-like behaviour in adult male mice exposed to fluoxetine early in life.

RATIONALE: Fluoxetine (Flx; brand names Prozac, Sarafem, Rapiflux), a selective serotonin reuptake inhibitor, is prescribed for the treatment of depression in pregnant women; however, this commonly prescribed medication could affect fetal brain development as Flx crosses the placenta. The available data concerning the anatomical and behavioural consequences of perinatal exposure to Flx during early development on adult behaviour are limited and often contradictory. OBJECTIVES: To further delineate the long-term behavioural effects of altering 5-HT during development, we examined the effects of perinatal Flx exposure on the behaviour of male mice as adults. METHODS: Dams were treated with approximately 25 mg/kg/day of Flx from embryonic day 15 to postnatal day 12, and the behaviour of the adult offspring was assessed. RESULTS: We found that perinatal Flx exposure leads to increased aggression, improved spatial memory, and reduced anxiety-like behaviour. This exposure did not cause memory deficits, changes in sensory processing, or changes in gross motor function. CONCLUSIONS: Our results suggest that while perinatal exposure to Flx may have long-term effects on adult behaviour, these effects appear limited and not necessarily detrimental.

Parent and family impact of raising a child with perinatal stroke.

BACKGROUND: Perinatal stroke is a leading cause of early brain injury, cerebral palsy, and lifelong neurological morbidity. No study to date has examined the impact of raising a child with perinatal stroke on parents and families. However, a large breadth of research suggests that parents, especially mothers, may be at increased risk for psychological concerns. The primary aim of this study was to examine the impact of raising a child with perinatal stroke on mothers' wellbeing. A secondary aim was to examine how caring for a child with perinatal stroke differentially affects mothers and fathers. METHODS: In Study I, a matched case-control design was used to compare the wellbeing of mothers of children with perinatal stroke and mothers of children with typical development. In Study II, a matched case-control design was used to compare mother-father dyads. Participants completed validated measures of anxiety and depression, stress, quality of life and family functioning, marital satisfaction, and marital distress. Parents of children with perinatal stroke also completed a recently validated measure of the psychosocial impact of perinatal stroke including guilt and blame outcomes. Disease severity was categorized by parents, validated by the Pediatric Stroke Outcome Measure (PSOM), and compared across the above outcomes in Study I. RESULTS: A total of 112 mothers participated in Study I (n = 56 per group; mean child age = 7.42 years), and 56 parents participated in Study II (n = 28 per group; mean child age = 8.25 years). In Study I, parent assessment of disease severity was correlated with PSOM scores (γ = 0.75, p < .001) and associated with parent outcomes. Mothers of children with mild conditions were indistinguishable from controls on the outcome measures. However, mothers of children with moderate/severe conditions had poorer outcomes on measures of depression, marital satisfaction, quality of life, and family functioning. In Study II, mothers and fathers had similar outcomes except mothers demonstrated a greater burden of guilt and higher levels of anxiety. CONCLUSIONS: Although most mothers of children with perinatal stroke adapt well, mothers of children with moderate/severe conditions appear to be at higher risk for psychological concerns.

Long-term outcomes of developmental exposure to fluoxetine: a review of the animal literature.

During and following pregnancy, women are at high risk of experiencing depression, for which fluoxetine (FLX; brand names Prozac, Sarafem, Rapiflux) is the most commonly prescribed treatment. An estimated 1.4-2.1% of pregnant women use this medication, which inhibits the reuptake of serotonin and thereby increases serotonergic activity at the synapse. Serotonin acts as a cue guiding numerous neurodevelopmental processes, and changes in the concentration of serotonin can disrupt normal in utero brain development and organization in humans and other animals, thus providing a mechanism by which maternal intake of FLX might alter neural development and ultimately behaviour. Despite this possibility, long-term alterations of behaviour and the brain have not been well studied in individuals exposed to FLX during pregnancy or soon after birth, perhaps because conducting such studies beyond infancy presents significant challenges. To remedy this problem, many researchers have turned to modelling the effects of developmental FLX exposure in non-human animals, primarily rodents. The body of literature on this topic has expanded considerably over the past several years, yet a comprehensive review is lacking. In order to fill this gap, we have summarized the findings of those studies describing the long-term behavioural and neurophysiological effects of FLX exposure in non-human animals in early development. We also discuss methodological considerations and common shortcomings of research in this area. The precise nature of the long-term effects of developmental FLX exposure remains difficult to specify, as these effects appear to be highly variable and dependent on numerous factors. Overall, however, it is clear that early FLX exposure in non-human animals can alter the development of the brain in ways that are relevant to behaviour in adulthood, decreasing exploration and social interaction, and in some cases altering anxiety- and depression-like behaviours..

Vesicular Zinc Modulates Cell Proliferation and Survival in the Developing Hippocampus.

In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic vesicles by zinc transporter 3 (ZnT3), has extensive effects on neuronal signalling and modulation. Vesicular zinc-focused research has mainly been directed to its role in the hippocampus, particularly in adult neurogenesis. However, whether vesicular zinc is involved in modulating neurogenesis during the early postnatal period has been less studied. As a first step to understanding this, we used ZnT3 knockout (KO) mice, which lack ZnT3 and, thus, vesicular zinc, to evaluate cell proliferation at three different age points spanning postnatal development (P6, P14, and P28). The survival and the neuronal phenotype of these cells was also assessed in adulthood. We found that male ZnT3 KO mice exhibited lower rates of cell proliferation at P14, but a greater number of these cells survived to adulthood. Additionally, significantly more cells labelled on P6 survived to adulthood in male and female ZnT3 KO mice. We also found sex-dependent differences, whereby male mice showed higher levels of cell proliferation at P28, as well as higher levels of cell survival for P14-labelled cells, compared to female mice. However, female mice showed greater percentages of neuronal differentiation for P14-labelled cells. Finally, we found significant effects of age of BrdU injections on cell proliferation, survival, and neuronal differentiation. Collectively, our results suggest that the loss of vesicular zinc affects normal proliferation and survival of cells born at different age points during postnatal development and highlight prominent sex- and age-dependent differences. Our findings provide the foundation for future studies to further probe the role of vesicular zinc in the modulation of developmental neurogenesis.

Environmental Enrichment Engages Vesicular Zinc Signaling to Enhance Hippocampal Neurogenesis.

Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic factor (mBDNF), but was otherwise dispensable under SH conditions. Using the Spatial Object Recognition task and the Morris Water task we show that, unlike WT mice, ZnT3 KO mice showed no improvements in spatial memory following EE. These experiments demonstrate that vesicular zinc is essential for the enhancement of adult hippocampal neurogenesis and behaviour following enrichment, supporting a role for zincergic neurons in contributing to experience-dependent plasticity in the hippocampus.

Lack of Vesicular Zinc Does Not Affect the Behavioral Phenotype of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation Mice.

Zinc is important in neural and synaptic development and neuronal transmission. Within the brain, zinc transporter 3 (ZnT3) is essential for zinc uptake into vesicles. Loss of vesicular zinc has been shown to produce neurodevelopmental disorder (NDD)-like behavior, such as decreased social interaction and increased anxiety- and repetitive-like behavior. Maternal immune activation (MIA) has been identified as an environmental factor for NDDs, such as autism spectrum disorders (ASDs) and schizophrenia (SZ), in offspring, which occurs during pregnancy when the mother's immune system reacts to the exposure to viruses or infectious diseases. In this study, we investigated the interaction effect of a genetic factor [ZnT3 knockout (KO) mice] and an environmental factor (MIA). We induced MIA in pregnant female (dams) mice during mid-gestation, using polyinosinic:polycytidylic acid (polyI:C), which mimics a viral infection. Male and female ZnT3 KO and wild-type (WT) offspring were tested in five behavioral paradigms: Ultrasonic Vocalizations (USVs) at postnatal day 9 (P9), Open Field Test, Marble Burying Test, three-Chamber Social Test, and Pre-pulse Inhibition (PPI) in adulthood (P60-75). Our results indicate that loss of vesicular zinc does not result in enhanced ASD- and SZ-like phenotype compared to WT, nor does it show a more pronounced phenotype in male ZnT3 KO compared to female ZnT3 KO. Finally, MIA offspring demonstrated an ASD- and SZ-like phenotype only in specific behavioral tests: increased calls emitted in USVs and fewer marbles buried. Our results suggest that there is no interaction between the loss of vesicular zinc and MIA induction in the susceptibility to developing an ASD- and SZ-like phenotype.

Larger cortical motor maps after seizures.

Expansion of motor maps occurs in both clinical populations with epilepsy and in experimental models of epilepsy when the frontal lobes are involved. We have previously shown that the forelimb area of the motor cortex undergoes extensive enlargement after seizures, although the extent to which many movement representation areas are altered is not clear. Here we hypothesize that movement representations in addition to the forelimb area will be enlarged after cortical seizures. To test our hypotheses, Long Evans Hooded rats received 20 sessions of callosal (or sham) kindling, and then were subjected to intracortical microstimulation to map several movement representations including the jaw, neck, forelimb, hindlimb, trunk and tail. We found significantly larger total map areas of several movement representations, including movements that could be evoked more posterior than they are in control rats. We also show the presence of more multiple movement sites and lower movement thresholds in kindled rats, suggesting that movements not only overlap and share cortical territory after seizures, but become present in formerly non-responsive sites as they become detectable with our intracortical microstimulation methodology. In summary, several motor map areas become larger after seizures, which may contribute to the interictal motor disturbances that have been documented in patients with epilepsy.

Zinc and cortical plasticity.

The divalent cation zinc is an essential element, having both universal and specified functions throughout the body. In the mammalian telencephalon, zinc has extensive effects on neurotransmission, affecting receptor function and second messenger systems. Through these means, it is often postulated that zinc has a fundamental role in regulating cortical synaptic function. Given that plasticity, that is, the morphological and physiological alterations that occur within neurons, is a defining characteristic of the brain, it is of particular interest to examine the mechanisms by which zinc might be involved in this process. In this review, the neurobiological characteristics of zinc will be discussed, including its distribution and the processes by which its homeostasis is regulated. As well, the substantial effects zinc may have on neuronal functioning will be examined. Finally, evidence gathered from electrophysiological, behavioural, and anatomical experiments are utilized to argue for a role of zinc in cortical plasticity.

Brain-derived Neurotrophic Factor and TrkB Levels in Mice that Lack Vesicular Zinc: Effects of Age and Sex.

In certain neurons, zinc ions are stored in synaptic vesicles by zinc transporter 3 (ZnT3). Vesicular zinc can then be released synaptically to modulate myriad targets. In vitro evidence indicates that these targets may include brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB). But the effects of vesicular zinc on BDNF and TrkB in the intact brain are unclear. Studies of mice that lack ZnT3 - and, as a result, vesicular zinc - have shown abnormalities in BDNF and TrkB levels, but results have been mixed and are therefore difficult to interpret. This might be caused by differences in the age or sex of mice tested. In the present study, we measured BDNF and TrkB levels in the hippocampus and neocortex, comparing wild type and ZnT3 knockout mice of both sexes at two ages (5 and 12 weeks). We also examined BDNF mRNA expression and protein levels at an intermediate age (8-10 weeks). We found that, regardless of age or sex, BDNF and TrkB protein levels did not differ between wild type and ZnT3 knockout mice. There were sex-specific differences in BDNF protein and mRNA expression, however. BDNF protein levels increased with age in female mice but not in males. And in females, but not males, ZnT3 KO mice exhibited great hippocampal BDNF mRNA expression than wild type mice. We conclude that, at least in naïve mice housed under standard laboratory conditions, elimination of vesicular zinc does not affect BDNF or TrkB protein levels.

Examination of Zinc in the Circadian System.

Zinc is a trace element that is essential for a large number of biological and biochemical processes in the body. In the nervous system zinc is packaged into synaptic vesicles by the ZnT3 transporter, and synaptic release of zinc can influence the activity of postsynaptic cells, either directly through its own cognate receptors, or indirectly by modulating activation of receptors for other neurotransmitters. Here, we explore the anatomical and functional aspects of zinc in the circadian system. Melanopsin-containing retinal ganglion cells in the mouse retina were found to colocalize ZnT3, indicating that they can release zinc at their synaptic targets. While the master circadian clock in the hamster suprachiasmatic nucleus (SCN) was found to contain, at best, sparse zincergic input, the intergeniculate leaflet (IGL) of hamsters and mice were found to have prominent zincergic input. Levels of zinc in these areas were not affected by time of day. Additionally, IGL zinc staining persisted following enucleation, indicating other prominent sources of zinc instead of, or in addition to, the retina. Neither enhancement nor chelation of free zinc at either the SCN or IGL altered circadian responses to phase-shifting light in hamsters. Finally, entrainment, free-running, and circadian responses to light were explored in mice lacking the ZnT3 gene. In every aspect explored, the ZnT3 knockout mice were not significantly different from their wildtype counterparts. These findings highlight the presence of zinc in areas critical for circadian functioning but have yet to identify a role for zinc in these areas.

Effects of enriched housing on the neuronal morphology of mice that lack zinc transporter 3 (ZnT3) and vesicular zinc.

In the central nervous system, certain neurons store zinc within the synaptic vesicles of their axon terminals. This vesicular zinc can then be released in an activity-dependent fashion as an intercellular signal. The functions of vesicular zinc are not entirely understood, but evidence suggests that it is important for some forms of experience-dependent plasticity in the brain. The ability of neurons to store and release vesicular zinc is dependent on expression of the vesicular zinc transporter, ZnT3. Here, we examined the neuronal morphology of mice that lack ZnT3. Brains were collected from mice housed under standard laboratory conditions and from mice housed in enriched environments - large, multilevel enclosures with running wheels, numerous objects and tunnels, and a greater number of cage mates. Golgi-Cox staining was used to visualize neurons for analysis of dendritic length and dendritic spine density. Neurons were analyzed from the barrel cortex, striatum, basolateral amygdala, and hippocampus (CA1). ZnT3 knockout mice, relative to wild type mice, exhibited increased basal dendritic length in the layer 2/3 pyramidal neurons of barrel cortex, independently of housing condition. Environmental enrichment decreased apical dendritic length in these same neurons and increased dendritic spine density on striatal medium spiny neurons. Elimination of ZnT3 did not modulate any of the effects of enrichment. Our results provide no evidence that vesicular zinc is required for the experience-dependent changes that occur in response to environmental enrichment. They are consistent, however, with recent reports suggesting increased cortical volume in ZnT3 knockout mice.

Enhanced plasticity in zincergic, cortical circuits after exposure to enriched environments.

Despite the plethora of reports that demonstrate plasticity in the mammalian cerebral cortex, the characterization of the cellular mechanisms that mediate it is sparse. Here, we show that the magnitude of the experience-dependent regulation of vesicular zinc is significantly increased through enriched-environment housing. Mice were reared either in a deprived environment and subsequently housed in deprived, minimally enriched, or enriched conditions after the removal of the c-row of vibrissae or reared in an enriched environment before and after vibrissae removal. Levels of vesicular zinc were assessed in deprived and nondeprived barrels 6 h to 14 d after vibrissae removal. We found that housing in enriched environmental conditions resulted in a greater change in vesicular zinc levels than did other housing conditions; however, this effect was dependent on both the magnitude and duration of enrichment. Our data indicate that enriched-environment housing has profound effects on the regulation of vesicular zinc that occurs concurrently with experience-dependent plasticity, suggesting a role for zinc in the multitude of cortical modifications associated with enriched environments.

Neonatal medial frontal cortex lesions disrupt circadian activity patterns.

The medial frontal cortex (MFC) is involved in the temporal organization of behaviour. It receives timing information from the master circadian clock in the suprachiasmatic nucleus (SCN), and exhibits daily oscillations in gene expression itself. In this study, we evaluate various properties of circadian rhythms of locomotor activity following neonatal or adult MFC aspiration lesions. Mice with neonatal lesions were more active during the day than mice with adult lesions and less active during the early night than both mice with adult lesions and control mice. Compared to controls, mice with neonatal lesions exhibited smaller phase delays to an early-night light pulse and marginally larger phase advances to a late-night light pulse. Mice with adult lesions did not differ from controls on either measure. The results suggest that the timing of behaviour is determined by an interaction between the MFC and the SCN and that injury early in life has a significant effect on the ability of animals to organize such behaviours.

Signaling by Synaptic Zinc is Required for Whisker-Mediated, Fine Texture Discrimination.

Zinc-containing terminals are found throughout the neocortex, concentrated predominantly in layers II/III, V, and VI. Synaptic zinc is a potent neurotransmitter/modulator and, therefore, may mediate inter- or intra-cortical integration of sensory information. We have previously shown that levels of synaptic zinc are rapidly modulated in somatosensory (barrel) cortex, in an experience- and activity-dependent manner. Zinc transporter 3 (ZnT3) knockout (KO) mice lack synaptic zinc and provide us with a good model to examine the contribution of synaptic zinc to barrel cortex-dependent behavior. In the present study, we show that ZnT3 KO mice display a marked decrease in acuity for whisker-dependent texture discrimination. ZnT3 KO mice were not able to discriminate between textures having an average particle diameter less than 300 µm while control mice were able to discriminate between textures having particle diameters separated by as little as 25 µm. This loss of texture discrimination acuity in ZnT3 KO mice was whisker-dependent and was observed in young (2 months-of-age) and older mice (12 months-of-age). These results show that zincergic signaling is necessary for the normal integration of somatosensory information.

Behavior of Adult 5-HT1A Receptor Knockout Mice Exposed to Stress During Prenatal Development.

Chronic maternal stress during pregnancy can have long-term, detrimental consequences for the offspring. An understanding of the mechanisms responsible for mediating these effects is essential for devising therapeutic interventions. Here, we examined whether serotonin 1A receptor (5-HT1AR) mediates the effects of maternal stress on the behavioral outcomes of the offspring as adults. Heterozygous (HET) mouse dams were bred with HET males and were randomly assigned to stress or control groups. Pregnant dams in the stress group were exposed to a regime of chronic unpredictable stress from embryonic day 7 to 18. At two months of age, groups of male and female wildtype (WT), HET, and knockout (KO) offspring underwent a comprehensive behavioral test battery that included tests of social behavior, memory, aggression, anxiety, sensorimotor information processing, and exploratory and risk assessment behaviors. Independent of genotype, prenatal stress resulted in a change in locomotor activity and fear memory in male mice and a change in prepulse inhibition in female animals. 5-HT1AR KO affected anxiety in male mice, and fear memory and prepulse inhibition in female mice. 5-HT1AR genotype moderated the effects of maternal prenatal stress exposure on social behavior of male offspring and on activity levels of female offspring. Our findings indicate that 5-HT1A receptor availability can affect outcomes of the offspring resulting from maternal prenatal stress exposure, and that these effects are sex-specific.

Elimination of vesicular zinc alters the behavioural and neuroanatomical effects of social defeat stress in mice.

Chronic stress can have deleterious effects on mental health, increasing the risk of developing depression or anxiety. But not all individuals are equally affected by stress; some are susceptible while others are more resilient. Understanding the mechanisms that lead to these differing outcomes has been a focus of considerable research. One unexplored mechanism is vesicular zinc - zinc that is released by neurons as a neuromodulator. We examined how chronic stress, induced by repeated social defeat, affects mice that lack vesicular zinc due to genetic deletion of zinc transporter 3 (ZnT3). These mice, unlike wild type mice, did not become socially avoidant of a novel conspecific, suggesting resilience to stress. However, they showed enhanced sensitivity to the potentiating effect of stress on cued fear memory. Thus, the contribution of vesicular zinc to stress susceptibility is not straightforward. Stress also increased anxiety-like behaviour but produced no deficits in a spatial Y-maze test. We found no evidence that microglial activation or hippocampal neurogenesis accounted for the differences in behavioural outcome. Volumetric analysis revealed that ZnT3 KO mice have larger corpus callosum and parietal cortex volumes, and that corpus callosum volume was decreased by stress in ZnT3 KO, but not wild type, mice.