Microglia depletion facilitates the display of maternal behavior and alters activation of the maternal brain network in nulliparous female rats.

The peripartum period is accompanied by peripheral immune alterations to promote a successful pregnancy. We and others have also demonstrated significant neuroimmune changes that emerge during late pregnancy and persist postpartum, most prominently decreased microglia numbers within limbic brain regions. Here we hypothesized that microglial downregulation is important for the onset and display of maternal behavior. To test this, we recapitulated the peripartum neuroimmune profile by depleting microglia in non-mother (i.e., nulliparous) female rats who are typically not maternal but can be induced to behave maternally towards foster pups after repeated exposure, a process called maternal sensitization. BLZ945, a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, was administered systemically to nulliparous rats, which led to ~75% decrease in microglia number. BLZ- and vehicle-treated females then underwent maternal sensitization and tissue was stained for ∆fosB to examine activation across maternally relevant brain regions. We found BLZ-treated females with microglial depletion met criteria for displaying maternal behavior significantly sooner than vehicle-treated females and displayed increased pup-directed behaviors. Microglia depletion also reduced threat appraisal behavior in an open field test. Notably, nulliparous females with microglial depletion had decreased numbers of ∆fosB+ cells in the medial amygdala and periaqueductal gray, and increased numbers in the prefrontal cortex and somatosensory cortex, compared to vehicle. Our results demonstrate that microglia regulate maternal behavior in adult females, possibly by shifting patterns of activity in the maternal brain network.

Chronic Stress Impairs the Structure and Function of Astrocyte Networks in an Animal Model of Depression.

Now astrocytes appear to be the key contributors to the pathophysiology of major depression. Evidence in rodents shows that chronic stress is associated with a decreased expression of astrocytic GFAP-immunoreactivity within the cortex in addition to changes in the complexity and length of astrocyte processes. Furthermore, postmortem brains of individuals with depression have revealed a decrease in astrocyte density. Notably, astrocytes are extensively coupled to one another through gap junctions to form a network, or syncytium, and we have previously demonstrated that syncytial isopotentiality is a mechanism by which astrocytes function as an efficient system with respect to brain homeostasis. Interestingly, the question of how astrocyte network function changes following chronic stress is yet to be elucidated. Here, we sought to examine the effects of chronic stress on network-level astrocyte (dys)function. Using a transgenic aldh1l1-eGFP astrocyte reporter mouse, a six-week unpredictable chronic mild stress (UCMS) paradigm as a rodent model of major depression, and immunohistochemical approaches, we show that the morphology of individual astrocytes is altered by chronic stress exposure. Additionally, in astrocyte syncytial isopotentiality measurement, we found that UCMS impairs the syncytial coupling strength of astrocytes within the hippocampus and prefrontal cortex-two brain regions that have been implicated in the regulation of mood. Together, these findings reveal that chronic stress leads to astrocyte atrophy and impaired gap junction coupling, raising the prospect that both individual and network-level astrocyte functionality are important in the etiology of major depression and other neuropsychiatric disorders.

Prenatal allergic inflammation in rats programs the developmental trajectory of dendritic spine patterning in brain regions associated with cognitive and social behavior.

Allergic inflammation during pregnancy increases risk for a diagnosis of neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) in the offspring. Previously, we found a model of such inflammation, allergy-induced maternal immune activation (MIA), produced symptoms analogous to those associated with neurodevelopmental disorders in rats, including reduced juvenile play behavior, hyperactivity, and cognitive inflexibility. These behaviors were preceded by perinatal changes in microglia colonization and phenotype in multiple relevant brain regions. Given the role that microglia play in synaptic patterning as well as evidence for altered synaptic architecture in neurodevelopmental disorders, we investigated whether allergic MIA altered the dynamics of dendritic spine patterning throughout key regions of the rat forebrain across neurodevelopment. Adult virgin female rats were sensitized to the allergen, ovalbumin, with alum adjuvant, bred, and allergically challenged on gestational day 15. Brain tissue was collected from male and female offspring on postnatal days (P) 5, 15, 30, and 100-120 and processed for Golgi-Cox staining. Mean dendritic spine density was calculated for neurons in brain regions associated with cognition and social behavior, including the medial prefrontal cortex (mPFC), basal ganglia, septum, nucleus accumbens (NAc), and amygdala. Allergic MIA reduced dendritic spine density in the neonatal (P5) and juvenile (P15) mPFC, but these mPFC spine deficits were normalized by P30. Allergic inflammation reduced spine density in the septum of juvenile (P30) rats, with an interaction suggesting increased density in males and reduced density in females. MIA-induced reductions in spine density were also found in the female basal ganglia at P15, as well as in the NAc at P30. Conversely, MIA-induced increases were found in the NAc in adulthood. While amygdala dendritic spine density was generally unaffected throughout development, MIA reduced density in both medial and basolateral subregions in adult offspring. Correlational analyses revealed disruption to amygdala-related networks in the neonatal animals and cortico-striatal related networks in juvenile and adult animals in a sex-specific manner. Collectively, these data suggest that communication within and between these cognitive and social brain regions may be altered dynamically throughout development after prenatal exposure to allergic inflammation. They also provide a basis for future intervention studies targeted at rescuing spine and behavior changes via immunomodulatory treatments.

Maternal allergic inflammation in rats impacts the offspring perinatal neuroimmune milieu and the development of social play, locomotor behavior, and cognitive flexibility.

Maternal systemic inflammation increases risk for neurodevelopmental disorders like autism, ADHD, and schizophrenia in offspring. Notably, these disorders are male-biased. Studies have implicated immune system dysfunction in the etiology of these disorders, and rodent models of maternal immune activation provide useful tools to examine mechanisms of sex-dependent effects on brain development, immunity, and behavior. Here, we employed an allergen-induced model of maternal inflammation in rats to characterize levels of mast cells and microglia in the perinatal period in male and female offspring, as well as social, emotional, and cognitive behaviors throughout the lifespan. Adult female rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally on gestational day 15 of pregnancy with OVA or saline. Allergic inflammation upregulated microglia in the fetal brain, increased mast cell number in the hippocampus on the day of birth, and conferred region-, time- and sex- specific changes in microglia measures. Additionally, offspring of OVA-exposed mothers subsequently exhibited abnormal social behavior, hyperlocomotion, and reduced cognitive flexibility. These data demonstrate the long-term effects of maternal allergic challenge on offspring development and provide a basis for understanding neurodevelopmental disorders linked to maternal systemic inflammation in humans.

Immune System Alterations and Postpartum Mental Illness: Evidence From Basic and Clinical Research.

The postpartum period is a time associated with high rates of depression and anxiety as well as greater risk for psychosis in some women. A growing number of studies point to aberrations in immune system function as contributing to postpartum mental illness. Here we review evidence from both clinical and animal models suggesting an immune component to postpartum depression, postpartum anxiety, and postpartum psychosis. Thus far, clinical data primarily highlights changes in peripheral cytokine signaling in disease etiology, while animal models have begun to provide insight into the immune environment of the maternal brain and how central inflammation may also be contributing to postpartum mental illnesses. Further research investigating peripheral and central immune function, along with neural and endocrine interactions, will be important in successfully developing novel prevention and treatment strategies for these serious disorders that impact a large portion of new mothers.

Sex differences in the effects of early life stress exposure on mast cells in the developing rat brain.

Early life stress leads to long lasting effects on behavior. Neuroimmune cells have been implicated as key mediators of experience-induced changes in brain and behavioral development, in that they are highly responsive to stress. Mast cells are one such type of neuroimmune cell, but little is known about their role in brain development or following early life stress. Here, we assessed the impact of three different early life stress exposure paradigms on mast cell dynamics in the developing brain of male and female rats, focusing on the hippocampus and hypothalamus, where most mast cells reside. We found that exposure to two weeks of chronic variable stress during gestation led to increased mast cell number and activation in the female offspring hypothalamus on the day of birth. Acute exposure to maternal separation stress on postnatal day (PN) 2 led to significant decreases in mast cells within the hypothalamus and hippocampus of females, but not males. In contrast, one week of exposure to brief daily maternal separation stress (e.g., handling), increased mast cell numbers in the female, but not male, hippocampus. We found significant sex differences in mast cell number and activation, including males having more mast cells than females in the hippocampus on the day of birth and males having significantly more degranulated mast cells on PN11. Thus, mast cells may be an unappreciated mediator of sex-specific brain development in response to early life perturbations.