Neuroplasticity Deficits Research Articles

Probiotic therapy modulates the brain-gut-liver microbiota axis in a mouse model of traumatic brain injury

The interplay between gut microbiota and host health is crucial for maintaining the overall health of the body and brain, and it is even more crucial how changes in the bacterial profile can influence the aftermath of traumatic brain injury (TBI). We studied the effects of probiotic treatment after TBI to identify potential changes in hepatic lipid species relevant to brain function. Bioinformatic analysis of the gut microbiota indicated a significant increase in the Firmicutes/Bacteroidetes ratio in the probiotic-treated TBI group compared to sham and untreated TBI groups. Although strong correlations between gut bacteria and hepatic lipids were found in sham mice, TBI disrupted these links, and probiotic treatment did not fully restore them. Probiotic treatment influenced systemic glucose metabolism, suggesting altered metabolic regulation. Behavioral tests confirmed memory improvement in probiotic-treated TBI mice. While TBI reduced hippocampal mRNA expression of CaMKII and CREB, probiotics reversed these effects yet did not alter BDNF mRNA levels. Elevated pro-inflammatory markers TNF-α and IL1-β in TBI mice were not significantly affected by probiotic treatment, pointing to different mechanisms underlying the probiotic benefits. In summary, our study suggests that TBI induces dysbiosis, alters hepatic lipid profiles, and preemptive administration of Lactobacillus helveticus and Bifidobacterium longum probiotics can counter neuroplasticity deficits and memory impairment. Altogether, these findings highlight the potential of probiotics for attenuating TBI's detrimental cognitive and metabolic effects through gut microbiome modulation and hepatic lipidomic alteration, laying the groundwork for probiotics as a potential TBI therapy.

ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling

Depression is a devastating mood disorder that causes significant disability worldwide. Current knowledge of its pathophysiology remains modest and clear biological markers are lacking. Emerging evidence from human and animal models reveals persistent alterations in endoplasmic reticulum (ER) homeostasis, suggesting that ER stress-related signaling pathways may be targets for prevention and treatment. However, the neurobiological basis linking the pathways involved in depression-related ER stress remains unknown. Here, we report that an induced model of ER stress in mouse serotonin (5-HT) neurons is associated with reduced Egr1-dependent 5-HT cellular activity and 5-HT neurotransmission, resulting in neuroplasticity deficits in forebrain regions and a depressive-like phenotype. Ketamine administration engages downstream eIF2α signaling to trigger rapid neuroplasticity events that rescue the depressive-like effects. Collectively, these data identify ER stress in 5-HT neurons as a cellular pathway involved in the pathophysiology of depression and show that eIF2α is critical in eliciting ketamine's fast antidepressant effects.

The mitochondrial quality control system: a new target for exercise therapeutic intervention in the treatment of brain insulin resistance-induced neurodegeneration in obesity.

Obesity is a major global health concern because of its strong association with metabolic and neurodegenerative diseases such as diabetes, dementia, and Alzheimer's disease. Unfortunately, brain insulin resistance in obesity is likely to lead to neuroplasticity deficits. Since the evidence shows that insulin resistance in brain regions abundant in insulin receptors significantly alters mitochondrial efficiency and function, strategies targeting the mitochondrial quality control system may be of therapeutic and practical value in obesity-induced cognitive decline. Exercise is considered as a powerful stimulant of mitochondria that improves insulin sensitivity and enhances neuroplasticity. It has great potential as a non-pharmacological intervention against the onset and progression of obesity associated neurodegeneration. Here, we integrate the current knowledge of the mechanisms of neurodegenration in obesity and focus on brain insulin resistance to explain the relationship between the impairment of neuronal plasticity and mitochondrial dysfunction. This knowledge was synthesised to explore the exercise paradigm as a feasible intervention for obese neurodegenration in terms of improving brain insulin signals and regulating the mitochondrial quality control system.

Beyond Motor Deficits: Environmental Enrichment Mitigates Huntington's Disease Effects in YAC128 Mice.

Huntington's disease (HD) is a neurodegenerative genetic disorder characterized by motor, psychiatric, cognitive, and peripheral symptoms without effective therapy. Evidence suggests that lifestyle factors can modulate disease onset and progression, and environmental enrichment (EE) has emerged as a potential approach to mitigate the progression and severity of neurodegenerative processes. Wild-type (WT) and yeast artificial chromosome (YAC) 128 mice were exposed to different EE conditions. Animals from cohort 1 were exposed to EE between postnatal days 21 and 60, and animals from cohort 2 were exposed to EE between postnatal days 60 and 120. Motor and non-motor behavioral tests were employed to evaluate the effects of EE on HD progression. Monoamine levels, hippocampal cell proliferation, neuronal differentiation, and dendritic arborization were also assessed. Here we show that EE had an antidepressant-like effect and slowed the progression of motor deficits in HD mice. It also reduced monoamine levels, which correlated with better motor performance, particularly in the striatum. EE also modulated neuronal differentiation in the YAC128 hippocampus. These results confirm that EE can impact behavior, hippocampal neuroplasticity, and monoamine levels in YAC128 mice, suggesting this could be a therapeutic strategy to modulate neuroplasticity deficits in HD. However, further research is needed to fully understand EE's mechanisms and long-term effects as an adjuvant therapy for this debilitating condition.

High-Fat Diet Consumption Induces Neurobehavioral Abnormalities and Neuronal Morphological Alterations Accompanied by Excessive Microglial Activation in the Medial Prefrontal Cortex in Adolescent Mice.

The association between a high-fat diet (HFD) consumption and emotional/cognitive disorders is widely documented. One distinctive feature of the prefrontal cortex (PFC), a kernel emotion- and cognition-related brain region, is its protracted adolescent maturation, which makes it highly vulnerable to the detrimental effects of environmental factors during adolescence. Disruption of the PFC structure and function is linked to emotional/cognitive disorders, especially those that emerge in late adolescence. A HFD consumption is common among adolescents, yet its potential effects on PFC-related neurobehavior in late adolescence and any related underlying mechanisms are yet to be established. In the present study, adolescent (postnatal days 28-56) male C57BL/6J mice were fed a control diet (CD) or a HFD and underwent behavioral tests in addition to Golgi staining and immunofluorescence targeting of the medial PFC (mPFC). The HFD-fed adolescent mice exhibited anxiety- and depression-like behavior and abnormal mPFC pyramidal neuronal morphology accompanied by alterations in microglial morphology indicative of a heightened state of activation and increased microglial PSD95+ inclusions signifying excessive phagocytosis of the synaptic material in the mPFC. These findings offer novel insights into the neurobehavioral effects due to adolescent HFD consumption and suggest a contributing role in microglial dysfunction and prefrontal neuroplasticity deficits for HFD-associated mood disorders in adolescents.

212. Examining Working Memory and Hippocampal Neuroplasticity Deficits in Patients with MDD: A MEG Study

212. Examining Working Memory and Hippocampal Neuroplasticity Deficits in Patients with MDD: A MEG Study

Ginsenoside-Rg1 mitigates cardiac arrest-induced cognitive damage by modulating neuroinflammation and hippocampal plasticity

Ginsenoside-Rg1 can effectively ameliorate mental disorders, but whether ginsenoside-Rg1 plays a neuroprotective role in cardiac arrest and cardiopulmonary resuscitation (CA/CPR)-induced cognitive impairment remains unclear. In this study, a 5-min asphyxia-based CA/CPR rat model was established to explore the mechanisms underlying the effects of ginsenoside-Rg1 (40 mg·kg-1·d-1, ip, 14 days) on its cognitive alterations. These CA/CPR rats displayed spatial learning and memory impairment in the Morris water maze, as reflected in the compromised basal synaptic transmission and long-term potentiation (LTP) at the Schaffer collateral of hippocampal CA1 area in vivo electrophysiology, whereas the ginsenoside-Rg1 remarkably mitigated these alterations. Next, we found that ginsenoside-Rg1 inhibited hippocampal neuroinflammation by alleviating the CA/CPR-induced hippocampal activation of microglia and astrocytes and the overexpression of related proinflammatory cytokines interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α). In addition, ginsenoside-Rg1 improved CA/CPR-induced hippocampal neuronal apoptosis, dendritic spines and synaptic ultrastructure defects as associated with the upregulation of the key synaptic regulatory proteins. Furthermore, ginsenoside-Rg1 could ameliorate CA/CPR-induced aberrant expression of the key regulators of hippocampal glutamate signaling pathways, excitatory amino acid transporter 2 (EAAT2), excitatory amino acid transporter 1 (EAAT1), Glutamine Synthetase (GS), GluN2B, and glutamate. In conclusion, ginsenoside-Rg1 exerts its neuroprotective effects by ameliorating hippocampus-dependent neuroglia activation-mediated neuroinflammation and neuroplasticity deficits, shedding new light on the therapeutic intervention of CA/CPR-related cognitive disorders.

Long-Term Potentiation-Like Visual Synaptic Plasticity Is Negatively Associated With Self-Reported Symptoms of Depression and Stress in Healthy Adults.

Long-term potentiation (LTP) is one of the most extensively studied forms of neuroplasticity and is considered the strongest candidate mechanism for memory and learning. The use of event-related potentials and sensory stimulation paradigms has allowed for the translation from animal studies to non-invasive studies of LTP-like synaptic plasticity in humans. Accumulating evidence suggests that synaptic plasticity as measured by stimulus-specific response modulation is reduced in neuropsychiatric disorders such as major depressive disorder (MDD), bipolar disorders and schizophrenia, suggesting that impaired synaptic plasticity plays a part in the underlying pathophysiology of these disorders. This is in line with the neuroplasticity hypothesis of depression, which postulate that deficits in neuroplasticity might be a common pathway underlying depressive disorders. The current study aims to replicate and confirm earlier reports that visual stimulus-specific response modulation is a viable probe into LTP-like synaptic plasticity in a large sample of healthy adults (n = 111). Further, this study explores whether impairments in LTP-like synaptic plasticity is associated with self-reported subclinical depressive symptoms and stress in a healthy population. Consistent with prior research, the current study replicated and confirmed reports demonstrating significant modulation of visual evoked potentials (VEP) following visual high-frequency stimulation. Current results further indicate that reduced LTP-like synaptic plasticity is associated with higher levels of self-reported symptoms of depression and perceived stress. This indicate that LTP-like plasticity is sensitive to sub-clinical levels of psychological distress, and might represent a vulnerability marker for the development of depressive symptoms.

Spontaneous Activity of CB2 Receptors Attenuates Stress-Induced Behavioral and Neuroplastic Deficits in Male Mice.

The monoaminergic theory of depression/anxiety disorders cannot fully explain the behavioral and neuroplastic changes observed after ADs chronic treatment. Endocannabinoid system, which comprises CB2 receptors, has been associated with the chronic effects of these drugs, especially in stressed mice. CB2-KO mice display more vulnerability to stressful stimuli. In the present study, we hypothesized that the behavioral and neuroplastic effects observed after repeated treatment with the AD escitalopram (Esc) in chronically stressed mice depend on CB2 receptor signaling. Male mice submitted to chronic unpredictable stress (CUS) paradigm (21 days) were treated daily with AM630 (0.01; 0.03 or 0.3 mg/kg, i.p) a CB2 receptor antagonist/inverse agonist. At e 19th day of the CUS protocol, mice were submitted to Open field test and Tail-suspension test to evaluate antidepressant-like behavior. At the end of the stress protocol, mice were submitted to Novel Suppressed Feeding test (day 22nd) to evaluate anxiety-like behavior. In a second series of experiments, male mice treated with Esc (10 mg/kg, daily, 21 days) in the presence or not of AM630 (0.30 mg/kg) were submitted to the same round of behavioral tests in the same conditions as performed in the dose-response curve protocol. Animals were then euthanized under deep anesthesia, and their brains/hippocampi removed for immunohistochemistry (Doublecortin-DCX) or Western Blot assay. Our results demonstrated that chronic treatment with AM630, a CB2 antagonist/inverse agonist, induces anxiolytic-like effects in stressed mice. Moreover, chronic reduction of CB2 receptor endogenous activity by AM630 attenuated the neuroplastic (potentiating stress-induced decreased expression of pro-BDNF, but enhanced pmTOR and DAGL expression in the hippocampus reduced in stressed mice), the antidepressant- but not the anxiolytic-like effects of Esc. AM630 alone or in combination with Esc decreased the expression of DCX + cell in both the subgranular and granular layers of the dentate gyrus (DG), indicating a general reduction of DCX + neuroblasts and a decrease in their migration through the DG layers. We suggest that the antidepressant-like behavior and the pro-neurogenic effect, but not the anxiolytic like behavior, promoted by Esc in stressed mice are, at least in part, mediated by CB2 receptors.

Hippocampal-specific insulin resistance elicits behavioral despair and hippocampal dendritic atrophy

Insulin resistance is a major contributor to the neuroplasticity deficits observed in patients with metabolic disorders. However, the relative contribution of peripheral versus central insulin resistance in the development of neuroplasticity deficits remains equivocal. To distinguish between peripheral and central insulin resistance, we developed a lentiviral vector containing an antisense sequence selective for the insulin receptor (LV-IRAS). We previously demonstrated that intra-hippocampal injection of this vector impairs synaptic transmission and hippocampal-dependent learning and memory in the absence of peripheral insulin resistance. In view of the increased risk for the development of neuropsychiatric disorders in patients with insulin resistance, the current study examined depressive and anxiety-like behaviors, as well as hippocampal structural plasticity in rats with hippocampal-specific insulin resistance. Following hippocampal administration of either the LV-control virus or the LV-IRAS, anhedonia was evaluated by the sucrose preference test, despair behavior was assessed in the forced swim test, and anxiety-like behaviors were determined in the elevated plus maze. Hippocampal neuron morphology was studied by Golgi-Cox staining. Rats with hippocampal insulin resistance exhibited anxiety-like behaviors and behavioral despair without differences in anhedonia, suggesting that some but not all components of depressive-like behaviors were affected. Morphologically, hippocampal-specific insulin resistance elicited atrophy of the basal dendrites of CA3 pyramidal neurons and dentate gyrus granule neurons, and also reduced the expression of immature dentate gyrus granule neurons. In conclusion, hippocampal-specific insulin resistance elicits structural deficits that are accompanied by behavioral despair and anxiety-like behaviors, identifying hippocampal insulin resistance as a key factor in depressive illness.

Physical Activity Reduces Clinical Symptoms and Restores Neuroplasticity in Major Depression.

Major depressive disorder (MDD) is the most common mental disorder and deficits in neuroplasticity are discussed as one pathophysiological mechanism. Physical activity (PA) enhances neuroplasticity in healthy subjects and improves clinical symptoms of MDD. However, it is unclear whether this clinical effect of PA is due to restoring deficient neuroplasticity in MDD. We investigated the effect of a 3-week PA program applied on clinical symptoms, motor excitability and plasticity, and on cognition in patients with MDD (N = 23), in comparison to a control intervention (CI; N = 18). Before and after the interventions, the clinical symptom severity was tested using self- (BDI-II) and investigator- (HAMD-17) rated scales, transcranial magnetic stimulation (TMS) protocols were used to test motor excitability and paired-associative stimulation (PAS) to test long-term-potentiation (LTP)-like plasticity. Additionally, cognitive functions such as attention, working memory and executive functions were tested. After the interventions, the BDI-II and HAMD-17 decreased significantly in both groups, but the decrease in HAMD-17 was significantly stronger in the PA group. Cognition did not change notably in either group. Motor excitability did not differ between the groups and remained unchanged by either intervention. Baseline levels of LTP-like plasticity in the motor cortex were low in both groups (PA: 113.40 ± 2.55%; CI: 116.83 ± 3.70%) and increased significantly after PA (155.06 ± 10.48%) but not after CI (122.01 ± 4.1%). Higher baseline BDI-II scores were correlated with lower levels of neuroplasticity. Importantly, the more the BDI-II score decreased during the interventions, the stronger did neuroplasticity increase. The latter effect was particularly strong after PA (r = −0.835; p < 0.001). The level of neuroplasticity related specifically to the psychological/affective items, which are tested predominantly in the BDI-II. However, the significant clinical difference in the intervention effects was shown in the HAMD-17 which focuses more on somatic/neurovegetative items known to improve earlier in the course of MDD. In summary, PA improved symptoms of MDD and restored the deficient neuroplasticity. Importantly, both changes were strongly related on the individual patients' level, highlighting the key role of neuroplasticity in the pathophysiology and the clinical relevance of neuroplasticity-enhancing interventions for the treatment of MDD.

Characterization of Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder Using Ketamine as an Experimental Medicine Probe †.

Comorbid posttraumatic stress disorder and major depressive disorder (PTSD + MDD) is the most common pathological response to trauma, yet despite their synergistic detriment to health, knowledge regarding the neurobiological mechanism underlying PTSD + MDD is extremely limited. This study proposes a novel model of PTSD + MDD that is built on biological systems shown to underlay PTSD + MDD and takes advantage of ketamine’s unique suitability to probe PTSD + MDD due to its rescue of stress-related neuroplasticity deficits. The central hypothesis is that changes in PTSD + MDD clinical symptoms are associated with functional connectivity changes and cognitive dysfunction and that ketamine infusions improve clinical symptoms by correction of functional connectivity changes and improvement in cognition. Participants with PTSD + MDD (n = 42) will be randomized to receive a series of six ketamine infusions or saline-placebo over three weeks. Pre/post-measures will include: (1) neuroimaging; (2) cognitive functioning task performance; and (3) PTSD, MDD, and rumination self-report measures. These measures will also be collected once in a trauma-exposed group including PTSD-only (n = 10), trauma-exposed-MDD (TE-MDD; n = 10), and healthy controls (HC, n = 21). Successful completion of the study will strongly support the concept of a biologically-based model of PTSD + MDD. The results will (1) identify functional imaging signatures of the mechanisms underpinning pathological responses to trauma, (2) shift focus from mono-diagnostic silos to unified biological and behavioral disease processes and, thus, (3) inform interventions to correct dysregulation of PTSD + MDD symptom clusters thereby supporting more precise treatments and better outcomes.

Auditory cognitive training improves prepulse inhibition in serine racemase mutant mice.

Evidence indicates that neuroplasticity-based cognitive training can improve cognition in patients with schizophrenia, but the individual response to training varies greatly between subjects. Hence, there is a need to understand the neurological underpinnings of cognitive training to reveal predictors of treatment response. D-serine is a crucial modulator of neuroplasticity, and decreased levels of D-serine may contribute to deficits in neuroplasticity in schizophrenia. Interestingly, we observed that training mice to identify auditory oddballs increased extracellular levels of D-serine in the hippocampus during training. Serine racemase (Srr) is the only source of brain D-serine; thus, it is possible that Srr may mediate the response to training. To test this hypothesis, we trained mice that have a mutated version of Srr (SrrY269*/SrrY269*) and reduced levels of D-serine in the same auditory training. SrrY269*/SrrY269* mice showed decreased performance during auditory training (defined as the capacity to discriminate an oddball during a sequence of tones). Importantly, auditory training improved prepulse inhibition (PPI) in SrrY269*/SrrY269* but not in wild-type mice. Finally, D-serine (100 mg/kg i.p.) given 30 min before training sessions to SrrY269*/SrrY269* mice improved training performance, but it did not enhance PPI. Taken together, our results show that D-serine is involved in the response to neuroplasticity-based auditory training and that PPI deficits can be improved by auditory oddball training even in the presence of neuroplasticity deficits.

Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of heme biosynthesis due to a pathogenic mutation in the Hmbs gene, resulting in half-normal activity of hydroxymethylbilane synthase. Factors that induce hepatic heme biosynthesis induce episodic attacks in heterozygous patients. The clinical presentation of acute attacks involves the signature neurovisceral pain and may include psychiatric symptoms. Here we used a knock-in mouse line that is biallelic for the Hmbs c.500G > A (p.R167Q) mutation with ~ 5% of normal hydroxymethylbilane synthase activity to unravel the consequences of severe HMBS deficiency on affective behavior and brain physiology. Hmbs knock-in mice (KI mice) model the rare homozygous dominant form of AIP and were used as tool to elucidate the hitherto unknown pathophysiology of the behavioral manifestations of the disease and its neural underpinnings. Extensive behavioral analyses revealed a selective depression-like phenotype in Hmbs KI mice; transcriptomic and immunohistochemical analyses demonstrated aberrant myelination. The uncovered compromised mitochondrial function in the hippocampus of knock-in mice and its ensuing neurogenic and neuroplastic deficits lead us to propose a mechanistic role for disrupted mitochondrial energy production in the pathogenesis of the behavioral consequences of severe HMBS deficiency and its neuropathological sequelae in the brain.

Targeting the Synapse in Alzheimer's Disease.

Dynamic gain and loss of synapses is fundamental to healthy brain function. While Alzheimer’s Disease (AD) treatment strategies have largely focussed on beta-amyloid and tau protein pathologies, the synapse itself may also be a critical endpoint to consider regarding disease modification. Disruption of mechanisms of neuronal plasticity, eventually resulting in a net loss of synapses, is implicated as an early pathological event in AD. Synaptic dysfunction therefore may be a final common biological mechanism linking protein pathologies to disease symptoms. This review summarizes evidence supporting the idea of early neuroplastic deficits being prevalent in AD. Changes in synaptic density can occur before overt neurodegeneration and should not be considered to uniformly decrease over the course of the disease. Instead, synaptic levels are influenced by an interplay between processes of degeneration and atrophy, and those of maintenance and compensation at regional and network levels. How these neuroplastic changes are driven by amyloid and tau pathology are varied. A mixture of direct effects of amyloid and tau on synaptic integrity, as well as indirect effects on processes such as inflammation and neuronal energetics are likely to be at play here. Focussing on the synapse and mechanisms of neuroplasticity as therapeutic opportunities in AD raises some important conceptual and strategic issues regarding translational research, and how preclinical research can inform clinical studies. Nevertheless, substrates of neuroplasticity represent an emerging complementary class of drug target that would aim to normalize synapse dynamics and restore cognitive function in the AD brain and in other neurodegenerative diseases.

140. Inflammatory Cytokines and Stem Cell Progeny in Major Depression

Inflammation and microglia activation may contribute to the neuroplasticity deficits we observed in subjects with major depression (MDD), including smaller anterior dentate gyrus (DG). MDD increases pro-inflammatory cytokines interleukin (IL)-1 and IL-6 in the peripheral blood and cerebral spinal fluid, and a depressive-like phenotype is induced by increasing inflammation. Interleukins have anti-neurogenic and pro-gliogenic effect in the hippocampus.

Facts and hypotheses about the programming of neuroplastic deficits by prenatal malnutrition.

Studies in rats have shown that a decrease in either protein content or total dietary calories results in molecular, structural, and functional changes in the cerebral cortex and hippocampus, among other brain regions, which lead to behavioral disturbances, including learning and memory deficits. The neurobiological bases underlying those effects depend at least in part on fetal programming of the developing brain, which in turn relies on epigenetic regulation of specific genes via stable and heritable modifications of chromatin. Prenatal malnutrition also leads to epigenetic programming of obesity, and obesity on its own can lead to poor cognitive performance in humans and experimental animals, complicating understanding of the factors involved in the fetal programming of neuroplasticity deficits. This review focuses on the role of epigenetic mechanisms involved in prenatal malnutrition-induced brain disturbances, which are apparent at a later postnatal age, through either a direct effect of fetal programming on brain plasticity or an indirect effect on the brain mediated by the postnatal development of obesity.

Amyloid aggravates tauopathy: stronger deficits in hippocampal and prefrontal neuroplasticity and fear memory in APP.V717IxTau.P301L vs. Tau.P301L mice

Amyloid aggravates tauopathy: stronger deficits in hippocampal and prefrontal neuroplasticity and fear memory in APP.V717IxTau.P301L vs. Tau.P301L mice

Physical Activity Modulates Common Neuroplasticity Substrates in Major Depressive and Bipolar Disorder.

Mood disorders (MDs) are chronic, recurrent mental diseases that affect millions of individuals worldwide. Although the biogenic amine model has provided some clinical utility, a need remains to better understand the interrelated mechanisms that contribute to neuroplasticity deficits in MDs and the means by which various therapeutics mitigate them. Of those therapeutics being investigated, physical activity (PA) has shown clear and consistent promise. Accordingly, the aims of this review are to (1) explicate key modulators, processes, and interactions that impinge upon multiple susceptibility points to effectuate neuroplasticity deficits in MDs; (2) explore the putative mechanisms by which PA mitigates these features; (3) review protocols used to induce the positive effects of PA in MDs; and (4) highlight implications for clinicians and researchers.

Abstract # 1772 Microglia-mediated dendritic remodeling is associated with alterations in neuron-derived signals after chronic unpredictable stress

Major depressive disorder is a recurring neuropsychiatric illness that affects up to 17% of the population and causes significant social and economic burden. Clinical and basic research show that depressive symptoms stem from neuroplasticity deficits in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Moreover, recent studies indicate that microglia, resident immune cells in the brain, play an important role in neuroplasticity. The primary objective of the current studies is to determine the role of microglia in neuroplasticity deficits and development of depressive-like behavior in male and female mice exposed to 14 days of chronic unpredictable stress (CUS). Initial immunohistology showed that microglia in male mice displayed an activated morphological phenotype in the mPFC, but appeared dystrophic in the HPC after CUS. In contrast, female mice showed no morphological changes in the mPFC or HPC. Consistent with these results, mRNA levels of colony stimulating factor-1 (CSF1) were increased in the mPFC, but reduced in the HPC after CUS. Furthermore, CUS increased CSF1 receptor expression in enriched microglia from male mice. To further examine neuron-microglia interactions transgenic Thy-1 (GFP) mice were used. Immunohistology analyses showed that CUS increased phagocytosis of pyramidal neuron elements in the mPFC of male mice. These findings suggest that stress-induced alterations in neuron-derived signals lead to microglia dysfunction and may contribute to microglia-mediated dendritic remodeling of pyramidal neurons in the mPFC.