Biology subjects

Bouknight, S. J.

Publications and source records attributed to Bouknight, S. J..

3 recordsLinked to original sources

bioRxiv2024

The role of locus coeruleus neuroimmune signaling in the response to social stress in female rats

Neuropsychiatric disorders that result from stress exposure are highly associated with central inflammation. Our previous work established that females selectively exhibit heightened proinflammatory cytokine production within the noradrenergic locus coeruleus (LC) along with a hypervigilant behavioral phenotype in response to witnessing social stress, and ablation of microglia using pharmacological techniques prevents this behavioral response. These studies were designed to further investigate the impact of stress-induced neuroimmune signaling on the long-term behavioral and neuronal consequences of social stress exposure in females using chemogenetics. We first characterized the use of an AAV-CD68-Gi-DREADD virus targeted to microglia within the LC and confirmed viral transduction, selectivity, and efficacy. Clozapine-n-oxide (CNO) was used for the suppression of microglial reactivity during acute and chronic exposure to vicarious/witness social defeat in female rats. Chemogenetic-mediated inhibition of microglial reactivity during stress blunted the neuroimmune response to stress and prevented both acute and long-term hypervigilant behavioral responses. Further, a history of microglial suppression during stress prevented the heightened LC activity typically observed in response to stress cues. These studies are among the first to use a chemogenetic approach to inhibit microglia within the female brain in vivo and establish LC inflammation as a key mechanism underlying the behavioral and neuronal responses to social stress in females.

neuroscience↗

bioRxiv2022

Site-Specific Knockdown of Microglia in the Locus Coeruleus Regulates Hypervigilant Responses to Social Stress in Female Rats

BackgroundWomen are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. MethodsMicroglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3g/side, n=5-6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25g/side, n=13-14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. ResultsIntra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1{beta} (IL-1{beta}). Further, the efficacy and selectivity of microinjected m-CLD was determined. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1{beta}. Intra-central amygdala m-CLD had no effect on witness stress-evoked behavior. ConclusionsThese studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses. HIGHLIGHTSO_LIIntra-LC LPS augments behavioral and physiological responses to social stress C_LIO_LIMannosylated liposomal clodronate site-specifically reduces microglial expression C_LIO_LIMicroglia within the locus coeruleus regulate stress-evoked behavior in female rats C_LI

neuroscience↗

bioRxiv2022

Estrogen receptor beta in the central amygdala regulates the deleterious behavioral and neuronal consequences of repeated social stress in female rats

While over 95% of the population has reported experiencing extreme stress or trauma, females of reproductive age develop stress-induced neuropsychiatric disorders at twice the rate of males. This suggests that estrogen may facilitate neural processes that increase stress susceptibility and underlie the heightened rates of these disorders, like depression and anxiety, that result from stress exposure in females. However, there is contradicting evidence in the literature regarding estrogens role in stress-related behavioral outcomes. Estrogen signaling through estrogen receptor beta (ER{beta}) has been traditionally thought of as anxiolytic, but recent studies suggest estrogen exhibits distinct effects in the context of stress. Furthermore, ER{beta} is found abundantly in many stress-sensitive brain loci, including the central amygdala (CeA), in which transcription of the vital stress hormone, corticotropin releasing factor (CRF), can be regulated by an estrogen response element. Therefore, these experiments sought to identify the role of CeA ER{beta} activity during stress on behavioral outcomes in naturally cycling, adult, female Sprague-Dawley rats. Rats were exposed to an ethological model of vicarious social stress, witness stress (WS), in which they experienced the sensory and psychological aspects of an aggressive social defeat encounter between two males. Following stress, rats exhibited stress-induced anxiety-like behaviors in the marble burying task, and, finally, brain analysis revealed increased ER{beta} and CRF specifically within the CeA following exposure to stress cues. Subsequent experiments were designed to target this receptor in the CeA using microinjections of the ER{beta} antagonist, PHTPP, prior to each stress session. Sucrose preference, acoustic startle, and marble burying tasks determined that blocking ER{beta} in the CeA during WS prevented the development of depressive-,anxiety-like, and hypervigilant behaviors. Additionally, brain analysis revealed a long-term decrease of intra-CeA CRF expression in PHTPP-treated WS rats compared to vehicle. These experiments indicate that ER{beta} signaling in the CeA, through its effects on CRF, contribute to the development of negative valence behaviors that result from exposure to repeated social stress in female rats.

neuroscience↗