Effects of sensory overstimulation in postpartum rats.

Research in rodents has shown that exposure to excessive early life audiovisual stimulation leads to altered anxiety-like behaviors and cognitive deficits. Since this period of stimulation typically begins prior to weaning, newborn rodents receive sensory overstimulation (SOS) as a litter within their home cage while the dam is present. However, the effects of SOS during the postpartum period remain unexplored. To this end, we adapted an SOS paradigm for use in rats and exposed rat dams and their litters from postpartum days (PD) 10-23. Maternal observations were conducted to determine whether SOS produced changes in positive and/or negative maternal behaviors. Next, we assessed changes in anxiety-like behavior and cognition by testing dams in the elevated zero maze, open field, and novel object recognition tests. To assess potential effects on HPA-axis function, levels of the stress hormone corticosterone (CORT) were measured approximately 1-week after the cessation of SOS exposure. Our results indicate increased nursing and licking in SOS dams compared to controls, although SOS dams also exhibited significant increases in pup dragging. Moreover, SOS dams exhibited reduced self-care behaviors and nest-building compared to control dams. No differences were found for anxiety-like behaviors, object recognition memory, or CORT levels. This study is the first to assess the impact of postpartum SOS exposure in rat dams. Our findings suggest an SOS-induced enhancement in positive caregiving, but limited impact in all other measures.

Behavioral responses to natural rewards in developing male and female rats.

Reward deficits are a hallmark feature of multiple psychiatric disorders and often recapitulated in rodent models useful for the study of psychiatric disorders, including those employing early life stress. Moreover, rodent studies have shown sex differences during adulthood in response to natural and drug rewards under normative conditions and in stress-based rodent models. Yet, little is known about the development of reward-related responses under normative conditions, including how these may differ in rats of both sexes during early development. Comparing reward-related behavioral responses between developing male and female rats may be useful for understanding how these processes may be affected in rodent models relevant to psychiatric disorders. To this end, we tested behavioral responses to natural rewards in male and female rats using sucrose consumption, sweet palatable food intake and social play tests at two timepoints (peripuberty, adolescence). Our results suggest comparable responses to consummatory and social rewards in male and female rats during peripuberty and adolescence as no sex differences were found for sucrose preference, chocolate candy intake or a subset of play behaviors (dorsal contacts, pins). These findings suggest that sex differences in response to these natural rewards emerge and may be more robust during adulthood.

Sex-dependent emergence of prepubertal social dysfunction and augmented dopamine activity in a neurodevelopmental rodent model relevant for schizophrenia.

Schizophrenia is a neurodevelopmental psychiatric disorder that often emerges in adolescence, is characterized by social dysfunction, and has an earlier onset in men. These features have been replicated in rats exposed to the mitotoxin methylazoxymethanol acetate (MAM) on gestational day (GD) 17, which as adults exhibit behavioral impairments and dopamine (DA) system changes consistent with a schizophrenia-relevant rodent model. In humans, social withdrawal is a negative symptom that often precedes disease onset and DA system dysfunction and is more pronounced in men. Children and adolescents at high-risk for schizophrenia exhibit social deficits prior to psychotic symptoms (i.e., prodromal phase), which can be used as a predictive marker for future psychopathology. Adult MAM rats also exhibit deficient social interaction, but less is known regarding the emergence of social dysfunction in this model, whether it varies by sex, and whether it is linked to disrupted DA function. To this end, we characterized the ontogeny of social and DA dysfunction in male and female MAM rats during the prepubertal period (postnatal days 33-43) and found sex-specific changes in motivated social behaviors (play, approach) and DA function. Male MAM rats exhibited reduced social approach and increased VTA DA neuron activity compared to saline-treated (SAL) males, whereas female MAM rats exhibited enhanced play behaviors compared to SAL females but no changes in social approach or VTA population activity during this period. These findings demonstrate sex differences in the emergence of social and DA deficits in the MAM model, in which females exhibit delayed emergence.

Sex differences in addiction-relevant behavioral outcomes in rodents following early life stress.

In humans, exposure to early life stress (ELS) is an established risk factor for the development of substance use disorders (SUDs) during later life. Similarly, rodents exposed to ELS involving disrupted mother-infant interactions, such as maternal separation (MS) or adverse caregiving due to scarcity-adversity induced by limited bedding and nesting (LBN) conditions, also exhibit long-term alterations in alcohol and drug consumption. In both humans and rodents, there is a range of addiction-related behaviors that are associated with drug use and even predictive of subsequent SUDs. In rodents, these include increased anxiety-like behavior, impulsivity, and novelty-seeking, altered alcohol and drug intake patterns, as well as disrupted reward-related processes involving consummatory and social behaviors. Importantly, the expression of these behaviors often varies throughout the lifespan. Moreover, preclinical studies suggest that sex differences play a role in how exposure to ELS impacts reward and addiction-related phenotypes as well as underlying brain reward circuitry. Here, addiction-relevant behavioral outcomes and mesolimbic dopamine (DA) dysfunction resulting from ELS in the form of MS and LBN are discussed with a focus on age- and sex-dependent effects. Overall, these findings suggest that ELS may increase susceptibility for later life drug use and SUDs by interfering with the normal maturation of reward-related brain and behavioral function.

Adult stress exposure blunts dopamine system hyperresponsivity in a neurodevelopmental rodent model of schizophrenia.

Stress is a major risk factor for the development of both schizophrenia and depression, and comorbidity between the two is common in schizoaffective disorders. However, the effects of stress exposure (i.e. chronic mild stress-CMS) on depression-related phenotypes in a neurodevelopmental model relevant to schizophrenia (i.e. methylazoxymethanol acetate-MAM) have yet to be explored and could provide insight into shared mechanisms of disease. To this end, we combined the prenatal MAM model with adult CMS exposure and explored the resultant pathophysiology using the social approach test (SAT), immobility in the forced swim test (FST) and amphetamine-induced hyperlocomotion (AIH) as depression- and schizophrenia-related endophenotypes and performed extracellular recordings of ventral tegmental area (VTA) DA neurons. MAM rats exhibited a reduction in social approach and increased VTA DA neuron activity compared to SAL rats or CMS groups. Separate cohorts of MAM animals were subjected to FST and AIH testing (counterbalanced order) or FST only. CMS groups exhibited increased FST immobility. Post-FST, both MAM groups (MAM-CON, MAM-CMS) exhibited blunted locomotor response to amphetamine compared with their SAL counterparts exposed to the same tests. Post-FST, MAM rats exhibited comparable VTA population activity to SAL rats, and CMS groups exhibited attenuated VTA population activity. Apomorphine administration results were consistent with the model suggesting that reductions in VTA DA neuron activity in MAM rats following FST exposure resulted from over-excitation, or depolarization block. These data suggest stress-induced DA downregulation in MAM rats, as FST exposure was sufficient to block the DA hyperresponsivity phenotype.

Postpartum scarcity-adversity disrupts maternal behavior and induces a hypodopaminergic state in the rat dam and adult female offspring.

Postpartum adversity is among the strongest predictors for the emergence of postpartum depression (PPD) in humans and a translational risk factor employed in rodent models. Parental care is disturbed under conditions of environmental adversity, including low resource environments, and in PPD. Nonetheless, the neural changes associated with these adversity-induced maladaptive behavioral states remain poorly understood. Postpartum scarcity-adversity can be modeled in rats by providing the dam with limited bedding and nesting (LBN) materials, which mimics the effects of a stressful low resource environment in potentiating maltreatment/neglect in humans. Indeed, LBN exposure from postpartum days (PD) 2-9 increased adverse maternal behaviors, impaired pup retrieval, and increased passive stress coping responses. Since mesolimbic dopamine (DA) activity is an important mechanism for motivated maternal behavior and is implicated in PPD, we assessed the impact of postpartum scarcity-adversity on in vivo electrophysiological properties of ventral tegmental area (VTA) DA neurons at two timepoints. We found reduced numbers of active VTA DA neurons in LBN dams at PD 9-10 but not PD-21, suggesting a transient impact on VTA population activity in LBN dams. Finally, we assessed the impact of early life scarcity-adversity on VTA DA function by conducting VTA recordings in adult female offspring and found a long-lasting attenuation in DA activity. These findings highlight a link between adversity-induced deficits in DA function and disrupted maternal behavior, suggesting the VTA/mesolimbic DA system as a potential mechanism by which postpartum scarcity-adversity drives aberrant maternal behavior, and early postnatal programming of adult VTA function in the offspring.

Dopamine downregulation in novel rodent models useful for the study of postpartum depression.

Postpartum depression (PPD) is the most common psychiatric disorder following childbirth and is characterized by maternal mood disturbances, impaired maternal responses, and disrupted caregiving- all of which negatively impact offspring development. Since PPD has detrimental consequences for both mother and child, clinical and preclinical research has focused on identifying brain changes associated with this disorder. In humans, PPD is linked to dysregulated mesolimbic dopamine (DA) system function and altered neural responses (i.e., decreased reward-related activity) to infant-related cues, which are considered hallmark features of PPD. In accordance, rodent models employing translational risk factors useful for the study of PPD have demonstrated alterations in mesolimbic DA system structure and function, and these changes are reviewed here. We also present two novel rodent models based on postpartum adversity exposure (i.e., pup removal, scarcity-adversity) which result in PPD-relevant behavioral changes (e.g., disrupted mother-infant interactions, deficits in maternal behavior, depressive-like phenotypes) and attenuated ventral tegmental area (VTA) DA neuron activity consistent with a hypodopaminergic state. Furthermore, we highlight open questions and future directions for these rodent models. In sum, human and rodent studies converge in showing blunted mesolimbic DA function (i.e., DA downregulation) in PPD. We propose that reduced activity of VTA DA neurons, resulting in downregulation of the mesolimbic DA system, interferes with reward-related processes necessary for maternal motivation and responsiveness. Thus, the mesolimbic DA system may constitute a therapeutic target for ameliorating reward-related deficits in PPD.

Bidirectional control of infant rat social behavior via dopaminergic innervation of the basolateral amygdala.

Social interaction deficits seen in psychiatric disorders emerge in early-life and are most closely linked to aberrant neural circuit function. Due to technical limitations, we have limited understanding of how typical versus pathological social behavior circuits develop. Using a suite of invasive procedures in awake, behaving infant rats, including optogenetics, microdialysis, and microinfusions, we dissected the circuits controlling the gradual increase in social behavior deficits following two complementary procedures-naturalistic harsh maternal care and repeated shock alone or with an anesthetized mother. Whether the mother was the source of the adversity (naturalistic Scarcity-Adversity) or merely present during the adversity (repeated shock with mom), both conditions elevated basolateral amygdala (BLA) dopamine, which was necessary and sufficient in initiating social behavior pathology. This did not occur when pups experienced adversity alone. These data highlight the unique impact of social adversity as causal in producing mesolimbic dopamine circuit dysfunction and aberrant social behavior.

Early Pup Removal Leads to Social Dysfunction and Dopamine Deficit in Late Postpartum Rats: Prevention by Social Support.

Offspring interaction is among the most highly motivated behaviors in maternal mammals and is mediated by mesolimbic dopamine (DA) system activation. Disruption or loss of significant social relationships is among the strongest individual predictors of affective dysregulation and depression onset in humans. However, little is known regarding the effects of disrupted mother-infant attachment (pup removal) in rat dams. Here, we tested the effects of permanent pup removal in rat dams, which were assigned to one of three groups on postpartum day (PD) 1: pups; pups removed, single-housed; or pups removed, co-housed with another dam who also had pups removed; and underwent a behavioral test battery during PD 21-23. In vivo electrophysiological recordings of ventral tegmental area (VTA) DA neurons were performed on PD 22 and 23 in a subset of animals. Pup removal did not impact sucrose consumption or anxiety-like behavior, but increased passive forced swim test (FST) coping responses. Pup-removal effects on social behavior and VTA activity were sensitive to social buffering: only single-housed dams exhibited reduced social motivation and decreased numbers of active DA neurons. Dams that had pups removed and were co-housed did not exhibit changes in social behavior or VTA function. Moreover, no changes in social behavior, FST coping, or VTA activity were found in socially isolated adult virgin females, indicating that effects observed in dams are specific to pup loss. This study showed that deprivation of species-expected social relationships (pups) during the postpartum precipitates an enduring negative affect state (enhanced passive coping, blunted social motivation) and attenuated VTA DA function in the dam, and that a subset of these effects is partially ameliorated through social buffering.

Adaptations in reward-related behaviors and mesolimbic dopamine function during motherhood and the postpartum period.

Initiation and maintenance of maternal behavior is driven by a complex interaction between the physiology of parturition and offspring stimulation, causing functional changes in maternal brain and behavior. Maternal behaviors are among the most robust and rewarding motivated behaviors. Mesolimbic dopamine (DA) system alterations during pregnancy and the postpartum enable enhanced reward-related responses to offspring stimuli. Here, we review behavioral evidence demonstrating postpartum rodents exhibit a bias towards pups and pup-related stimuli in reward-related tasks. Next, we provide an overview of normative adaptations in the mesolimbic DA system induced by parturition and the postpartum, which likely mediate shifts in offspring valence. We also discuss a causal link between dopaminergic dysfunction and disrupted maternal behaviors, which are recapitulated in postpartum depression (PPD) and relevant rodent models. In sum, mesolimbic DA system activation drives infant-seeking behavior and strengthens the mother-infant bond, potentially representing a therapeutic target for reward-related deficits in PPD.

Postpartum changes in affect-related behavior and VTA dopamine neuron activity in rats.

The onset of motherhood is accompanied by alterations in emotional and affective behaviors. Many new mothers experience transient and mild depressive symptoms that typically resolve spontaneously (i.e. postpartum blues) but increase the risk for postpartum depression (PPD). There is little data regarding the neural adaptations occurring in response to parturition and shortly after birth that may be associated with these affective changes. Although the dopamine (DA) system is involved in affect, maternal motivation and PPD, little is known about postpartum DA function. We compared affective behavior in virgin and postpartum adult female rats at early and late time points. In vivo extracellular recordings of VTA DA neurons were performed to evaluate 3 parameters: number of active DA neurons (i.e. population activity), firing rate, and firing pattern. Compared with virgins, postpartum rats exhibited increased anxiety-like behavior in the elevated plus maze at 1-day postpartum; reduced social motivation at 1- and 3-days postpartum, reduced anxiety-like behavior in the novelty suppressed feeding test throughout the first week postpartum and increased forced swim test immobility at 1-day postpartum. 1- and 3-day postpartum females exhibited attenuated VTA population activity without changes in firing rate or pattern. None of these effects were observed in late postpartum females when compared with virgins. These data suggest that parturition induces time-dependent changes in a subset of affect-related behaviors and DA function during the postpartum period in rodents, with early postpartum females exhibiting depression-related phenotypes (i.e. low social motivation, higher immobility, blunted DA activity).

Antidepressant effects of ketamine on depression-related phenotypes and dopamine dysfunction in rodent models of stress.

Depression, the most prevalent psychiatric disorder, is characterized by increased negative affect (i.e. depressed mood) and reduced positive affect (i.e. anhedonia). Stress is a risk factor for depression in humans, and animal models of chronic stress are typically used to study neurobehavioral alterations relevant to depression. Common behavioral outcomes in rodent models of chronic stress include anhedonia, social dysfunction and behavioral despair. For example, chronically stressed rodents exhibit reduced reward preference, as measured by a loss of preference for sucrose solutions and time spent interacting with a novel conspecific, while also exhibiting less time struggling against inescapable stressors (e.g. forced swim, tail suspension). In both humans and rodents, anhedonia is associated with dysfunction of the dopamine (DA) system. Unlike traditional antidepressants, which are limited by inadequate efficacy and delayed therapeutic response, acute ketamine administration rapidly alleviates depressive symptoms in humans and reverses stress-induced changes in animal models. These effects are partially mediated via actions on the DA system. This review summarizes the clinical effects of ketamine, the neurobiological underpinnings of depression with a focus on DA dysfunction, as well as antidepressant effects of ketamine on depression-related endophenotypes (i.e. anhedonia, despair) and ventral tegmental area (VTA) activity in rodent models of repeated stress. Moreover, we discuss evidence regarding sex differences in ketamine's antidepressant effects, wherein females appear to be more sensitive to lower dose ketamine, as well as novel findings suggesting that ketamine has prophylactic effects with regard to protection against the neurobehavioral impact of future stressors.

Enhancing Executive Functions Through Social Interactions: Causal Evidence Using a Cross-Species Model.

It has long been theorized that humans develop higher mental functions, such as executive functions (EFs), within the context of interpersonal interactions and social relationships. Various components of social interactions, such as interpersonal communication, perspective taking, and conforming/adhering to social rules, may create important (and perhaps even necessary) opportunities for the acquisition and continued practice of EF skills. Furthermore, positive and stable relationships facilitate the development and maintenance of EFs across the lifespan. However, experimental studies investigating the extent to which social experiences contribute causally to the development of EFs are lacking. Here, we present experimental evidence that social experiences and the acquisition of social skills influence the development of EFs. Specifically, using a rat model, we demonstrate that following exposure to early-life adversity, a socialization intervention causally improves working memory in peri-adolescence. Our findings combined with the broader literature promote the importance of cultivating social skills in support of EF development and maintenance across the lifespan. Additionally, cross-species research will provide insight into causal mechanisms by which social experiences influence cognitive development and contribute to the development of biologically sensitive interventions.

Corticosterone administration targeting a hypo-reactive HPA axis rescues a socially-avoidant phenotype in scarcity-adversity reared rats.

It is well-established that children from low-income, under-resourced families are at increased risk of altered social development. However, the biological mechanisms by which poverty-related adversities can "get under the skin" to influence social behavior are poorly understood and cannot be easily ascertained using human research alone. This study utilized a rodent model of "scarcity-adversity," which encompasses material resource deprivation (scarcity) and reduced caregiving quality (adversity), to explore how early-life scarcity-adversity causally influences social behavior via disruption of developing stress physiology. Results showed that early-life scarcity-adversity exposure increased social avoidance when offspring were tested in a social approach test in peri-adolescence. Furthermore, early-life scarcity-adversity led to blunted hypothalamic-pituitary-adrenal (HPA) axis activity as measured via adrenocorticotropic hormone (ACTH) and corticosterone (CORT) reactivity following the social approach test. Western blot analysis of brain tissue revealed that glucocorticoid receptor levels in the dorsal (but not ventral) hippocampus and medial prefrontal cortex were significantly elevated in scarcity-adversity reared rats following the social approach test. Finally, pharmacological repletion of CORT in scarcity-adversity reared peri-adolescents rescued social behavior. Our findings provide causal support that early-life scarcity-adversity exposure negatively impacts social development via a hypocorticosteronism-dependent mechanism, which can be targeted via CORT administration to rescue social behavior.

Female rats are resistant to the long-lasting neurobehavioral changes induced by adolescent stress exposure.

Stress during adolescence is a risk factor for neuropsychiatric diseases, including schizophrenia. We recently observed that peripubertal male rats exposed to a combination of daily footshock plus restraint stress exhibited schizophrenia-like changes. However, numerous studies have shown sex differences in neuropsychiatric diseases as well as on the impact of coping with stress. Thus, we decided to evaluate, in adolescent female rats, the impact of different stressors (restraint stress [RS], footshock [FS], or the combination of FS and RS [FS+RS]) on social interaction (3-chamber social approach test/SAT), anxiety responses (elevated plus-maze/EPM), cognitive function (novel object recognition test/NOR), and dopamine (DA) system responsivity by evaluating locomotor response to amphetamine and in vivo extracellular single unit recordings of DA neurons in the ventral tegmental area (VTA) in adulthood. The impact of FS+RS during early adulthood was also investigated. Adolescent stress had no impact on social behavior, anxiety, cognition and locomotor response to amphetamine. In addition, adolescent stress did not induce long-lasting changes in VTA DA system activity. However, a decrease in the firing rate of VTA DA neurons was found 1-2 weeks post-adolescent stress. Similar to adolescent stress, adult stress did not induce long-lasting behavioral deficits and changes in VTA DA system activity, but FS+RS decreased VTA DA neuron population activity 1-2 weeks post-adult stress. Our results are consistent with previous studies showing that female rodents appear to be more resilient to developmental stress-induced persistent changes than males and may contribute to the delayed onset and lesser severity of schizophrenia in females.

Stress: Influence of sex, reproductive status and gender.

Emerging evidence from the preclinical and human research suggests sex differences in response to different types of stress exposure, and that developmental timing, reproductive status, and biological sex are important factors influencing the degree of HPA activation/function. Here we review data regarding: i) sex differences in behavioral and neural responses to uncontrollable and controllable stressors; ii) distinct trajectories of behavioral development and HPA-axis function in male and female rats following adolescent stress exposure; iii) normative changes in behavior and dopamine function in early postpartum rats; iv) aberrant HPA-axis function and its link to abnormal behaviors in two independent, preclinical mouse models of postpartum depression; and, v) data indicating that gender, in addition to sex, is an important determinant of stress reactivity in humans. Based on these findings, we conclude it will be important for future studies to investigate the short and long-term effects of a wide variety of stressors, how these effects may differ according to developmental timing and in relation to gonadal function, the relationship between aberrant HPA-axis activity during the postpartum and mood disorders, and influences of both sex and gender on stress reactivity in humans.

Diazepam reverses increased anxiety-like behavior, social behavior deficit, and dopamine dysregulation following withdrawal from acute amphetamine.

Psychostimulants such as amphetamine (AMPH) increase dopamine (DA) release from ventral tegmental area (VTA) neurons, which is associated with their acute reinforcing actions. This positive state is followed by a negative affective state during the withdrawal period each time the drug is taken (i.e., opponent process theory). AMPH withdrawal is accompanied by symptoms of anxiety and depression, which are associated with DA system dysfunction in humans and animal models. Most studies have focused on the negative affective state after withdrawal from chronic drug administration; yet, this negative state appears even after a drug is taken for the first time in both humans and rodents. In rats, withdrawal from a single dose of AMPH (2 mg/kg) increases forced swim test immobility and decreases the number of spontaneously active VTA DA neurons up to 48 h post-withdrawal. In the current study, acute AMPH withdrawal was found to increase anxiety-like behavior in the elevated plus maze (EPM), reduce social cage time in the three-chambered social approach test (SAT), and attenuate VTA population activity. The effects of diazepam, a drug commonly used to treat anxiety disorders, were tested on anxiety-like and social behavior as well as VTA DA neuron activity following acute AMPH withdrawal. A single (5 mg/kg) dose of diazepam circumvented the neurobehavioral effects induced by acute AMPH withdrawal, as demonstrated by increased open arm time and social cage time as well as normalized VTA DA activity comparable to controls, suggesting that these neurobehavioral effects of acute AMPH withdrawal reflect an anxiety-like state.

Understanding pup affective state through ethologically significant ultrasonic vocalization frequency.

Throughout life, rats emit ultrasonic vocalizations (USV) when confronted with an aversive situation. However, the conditions classically used to elicit USV vary greatly with the animal's age (isolation from the dam in infancy, versus nociceptive stimulation in adults). The present study is the first to characterize USV responses to the same aversive event throughout development. Specifically, infant, juvenile and adult rats were presented with mild foot-shocks and their USV frequency, duration, and relationship with respiration and behavior were compared. In juvenile and adult rats, a single class of USV is observed with an age-dependent main frequency and duration (30 kHz/400 ms in juveniles, 22 kHz/900 ms in adults). In contrast, infant rat USV were split into two classes with specific relationships with respiration and behavior: 40 kHz/300 ms and 66 kHz/21 ms. Next, we questioned if these infant USV were also emitted in a more naturalistic context by exposing pups to interactions with the mother treating them roughly. This treatment enhanced 40-kHz USV while leaving 66-kHz USV unchanged suggesting that the use of USV goes far beyond a signal studied in terms of amount of emission, and can inform us about some aspects of the infant's affective state.

Sex-Dependent Effects of Stress on Immobility Behavior and VTA Dopamine Neuron Activity: Modulation by Ketamine.

Background: Stress constitutes a risk factor across several psychiatric disorders. Moreover, females are more susceptible to stress-related disorders, such as depression, than males. Although dopamine system underactivation is implicated in the pathophysiology of depression, little is known about the female dopamine system at baseline and post-stress. Methods: The effects of chronic mild stress were examined on ventral tegmental area dopamine neuron activity and forced swim test immobility by comparing male and female rats. The impact of a single dose of the rapid antidepressant ketamine (10 mg/kg, i.p.) on forced swim test immobility and ventral tegmental area function was then tested. Results: Baseline ventral tegmental area dopamine activity was comparable in both sexes. At baseline, females exhibited roughly double the forced swim test immobility duration than males, which corresponded to ~50% decrease in ventral tegmental area dopamine population activity compared with similarly treated (i.e., post-forced swim test) males. Following chronic mild stress, there was greater immobility duration in both sexes and reduced ventral tegmental area dopamine neuron activity by approximately 50% in males and nearly 75% in females. Ketamine restored behavior and post-forced swim test ventral tegmental area dopamine activity for up to 7 days in females as well as in both male and female chronic mild stress-exposed rats. Conclusions: These data suggest increased female susceptibility to depression-like phenotypes (i.e., greater immobility, ventral tegmental area hypofunction) is associated with higher dopamine system sensitivity to both acute and repeated stress relative to males. Understanding the neural underpinnings of sex differences in stress vulnerability will provide insight into mechanisms of disease and optimizing therapeutic approaches in both sexes.

Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM model.

Adolescence is a time of extensive neuroanatomical, functional and chemical reorganization of the brain, which parallels substantial maturational changes in behavior and cognition. Environmental factors that impinge on the timing of these developmental factors, including stress and drug exposure, increase the risk for psychiatric disorders. Indeed, antecedents to affective and psychotic disorders, which have clinical and pathophysiological overlap, are commonly associated with risk factors during adolescence that predispose to these disorders. In the context of schizophrenia, psychosis typically begins in late adolescence/early adulthood, which has been replicated by animal models. Rats exposed during gestational day (GD) 17 to the mitotoxin methylazoxymethanol acetate (MAM) exhibit behavioral, pharmacological, and anatomical characteristics consistent with an animal model of schizophrenia. Here we provide an overview of adolescent changes within the dopamine system and the PFC and review recent findings regarding the effects of stress and cannabis exposure during the peripubertal period as risk factors for the emergence of schizophrenia-like deficits. Finally, we discuss peripubertal interventions appearing to circumvent the emergence of adult schizophrenia-like deficits.