Postoperative cognitive dysfunction (POCD) is a common and persistent complication in aging individuals following surgery, particularly when opioids are used for perioperative pain management. Although opioids are widely administered in the perioperative setting, the mechanisms by which they contribute to long-term cognitive impairment remain poorly understood. Here, using an aged rat model of surgery with perioperative morphine administration, we investigated how synaptic, axonal, and mitochondrial abnormalities contribute to persistent hippocampal memory deficits, and evaluated therapeutic strategies targeting neuroinflammation and mitochondrial dysfunction. We found that these memory impairments were not attributable to systemic illness or gross dendritic degeneration. Instead, surgery and morphine-treated animals exhibited selective reductions in dendritic spine subtypes associated with synaptic stability, impaired late-phase long-term potentiation, and blunted experience-dependent upregulation of the AMPA receptor subunit GluA1. These synaptic alterations were accompanied by elevated circulating neurofilament light chain (Nf-L), indicating sustained axonal perturbation. Surgery and morphine treatment also produced persistent hippocampal mitochondrial dysfunction, characterized by impaired oxidative phosphorylation, reduced respiratory reserve capacity, and increased DNA oxidation. These effects were not observed in liver tissue, arguing against a widespread mitochondrial deficit. Pharmacological inhibition of central TLR4 signaling at the time of surgery, which previously rescued the memory deficit, attenuated oxidative stress and partially restored mitochondrial function, implicating early neuroinflammatory signaling in the development of long-term mitochondrial impairment. Finally, targeted mitochondrial rejuvenation with SS-31 four weeks post-surgery robustly rescued hippocampal-dependent memory and normalized mitochondrial respiratory function despite persistently elevated DNA oxidation and Nf-L. Together these findings identify sustained hippocampal mitochondrial dysfunction as a key mechanistic substrate underlying long-term cognitive deficits following surgery and morphine exposure in aged rats, and highlight mitochondrial bioenergetics as a promising therapeutic target for POCD.

7 % of pregnant people use opioids. Opioid use during pregnancy can negatively impact maternal and offspring health. Medications for opioid use disorder (MOUD), commonly buprenorphine, are the recommended treatment for opioid use disorder during pregnancy to prevent cycles of withdrawal and relapse. In addition to effects on opioid receptors, opioids have strong binding affinity to toll-like receptor (TLR) 4, an immune cell receptor, and thereby impact neuroinflammatory signaling. We have previously shown that neuroimmune alterations are important for the display of maternal behavior. Here, we used a rodent model to assess the impact of chronic peripartum opioid exposure or MOUD on maternal caregiving and neuroinflammation in the postpartum brain. Female rats were exposed to vehicle (VEH), buprenorphine (BUP) to model MOUD, or oxycodone (OXY), to model peripartum drug use, before, during, and after pregnancy. Opioid exposure reduced gestation length and maternal weight gain. Postpartum maternal caretaking behaviors, including pup retrieval, huddling and nursing, and pup-directed sniffing and licking, were reduced in opioid-exposed mothers. Following behavioral testing, tissue was collected from brain regions important for maternal caretaking, including the prefrontal cortex (PFC), nucleus accumbens (NAc), preoptic area (POA), amygdala (AMY), and periaqueductal grey (PAG). Immunofluorescent labeling showed that BUP increased astrocyte labeling, while OXY increased microglia labeling in the PAG, but not other regions. Gene expression analysis also showed regional and treatment differences in immune transcripts. BUP and OXY increased TLR4 in the PFC. BUP increased TNF in the NAc but decreased IL1 beta in the POA. OXY increased CD68 in the POA, and IL1 beta, TNF, and TLR4 in the PAG. Together, these results provide novel evidence of peripartum neuroimmune alterations following chronic opioid exposure that could be mediating maternal care deficits. This work provides a foundation to explore the extent to which modulation of neuroimmune activation may be a potential intervention for caregiving deficits in mothers exposed to opioids during pregnancy.

Adolescence is a period of protracted neurodevelopment, during which the prefrontal cortex (PFC) undergoes significant remodeling. Microglia are integral to neurodevelopment and are sensitive to gonadal hormones, which increase during adolescence. Microglia and gonadal hormones can interact to influence adolescent development of the PFC (or medial prefrontal cortex [mPFC] in rodents). In females, gonadal hormones can be perturbed by using hormonal contraceptives (HCs). We predicted that HC administration over adolescence could affect microglia, other immunocompetent cells, and the neuroimmune environment of the developing mPFC. We also assessed HC effects on neuroimmune measures in the hippocampus, as the hippocampus also matures throughout adolescence and is sensitive to ovarian hormones. Intact post-pubertal female Sprague-Dawley rats received daily subcutaneous injections of vehicle or 10 ug ethinyl estradiol + 20 ug levonorgestrel (HCs) throughout adolescence from postnatal day (PND) 35-56. On PND 57 or 58, brains were collected for immunohistochemistry and qPCR. In the mPFC, HC-treated rats showed less Iba1 (microglia) immunolabeling and fewer Iba1+ cells. HC treatment also altered microglia morphology and reduced the spacing between microglia in the mPFC. In the hippocampus, HC-treated rats had reduced Iba1 immunolabeling in the dorsal CA1 and reductions in microglial cell complexity in dorsal CA1, ventral CA1, and ventral CA3. There were no effects of HCs on GFAP (astrocyte) immunolabeling in the mPFC or on astrocytes in any hippocampal subregion analyzed, except an increase in astrocyte number in the dorsal dentate gyrus. mPFC expression of genes related to phagocytosis (Cd68, Trem2) and neuroimmune signaling (Cx3cr1, Cx3cl1) were reduced in rats treated with HCs, but no gene expression changes were seen in the hippocampus. These data provide the first evidence that HCs given during the critical developmental period of adolescence can affect microglia properties in limbic brain regions.

Millions of people take hormonal contraceptives (HCs), often starting during adolescence when ovarian hormones influence brain and behavioral maturation. However, there is a fundamental lack of information about the neurobehavioral consequences of hormonal alterations via adolescent HC use. To begin addressing this gap, we validated a rodent model of adolescent HC administration and characterized its impact on endocrine, transcriptional, and behavioral endpoints. Cohorts of intact post-pubertal female Sprague-Dawley rats received daily subcutaneous injections of either vehicle or HC [10 μg ethinyl estradiol (EE) + 20 μg levonorgestrel (LNG)] for the duration of adolescence from postnatal day (PND) 35 to PND56. Blood and brain tissue was collected at PND57. Other cohorts received daily injections of vehicle or HC from PND35 until behavioral assays were completed on PND57-64. HC treatment was effective, as vaginal lavage indicated disrupted estrous cycling and ELISA indicated suppressed serum luteinizing hormone in HC-treated rats. Liquid chromatography-mass spectrometry analysis showed EE and LNG in serum and brain as well as diminished serum and brain levels of allopregnanolone and testosterone in HC-treated rats. NanoString nCounter analysis indicated that adolescent HC administration impacted expression of genes related to synapses, white matter, neuroimmune, monoamine, and hormone signaling in the hypothalamus and medial prefrontal cortex. While no effects of HCs were seen on sociability in the social preference test or stress coping behavior in the forced swim test, adolescent HC administration diminished risk-assessment behaviors in the novelty-induced hypophagia paradigm and altered anxiety-like behavior in the open field test and elevated plus maze. Overall, these data suggest that exposure to contraceptive hormones during the critical developmental period of adolescence may shape the brain and behavior.

Postpartum depression (PPD) affects 20 % of new mothers. Little is known about what contributes to this prevalence, though one of the strongest risk factors for developing PPD is stress during pregnancy. Pregnancy and the postpartum period are accompanied by dramatic changes in the endocrine, nervous, and immune systems, which may confer heightened vulnerability to maternal mental illness. Microglia, the brain's main immune cells, are important for displaying maternal behaviors. Environmental insults to microglia, such as stress, lead to hormonal dysregulation and aberrant synaptic pruning, both of which have been implicated in the pathophysiology of mood disorders like depression. Given these links, we hypothesized that stress during pregnancy would lead to dysregulated neuroimmune and endocrine profiles and produce synaptic changes in the maternal brain. We used a 2-week variable stress model in pregnancy and assessed neuroimmune changes in the nucleus accumbens (NAc), a brain region that regulates functions impaired in PDD including mood and maternal caregiving. Peripheral hormones and cytokines were also measured. While peripheral cytokine levels were not affected by stress exposure, gestational stress induced central immune changes in the NAc of maternal rats. This included increased microglia immunolabeling and changes in pro- and anti-inflammatory transcripts measured by a Nanostring nCounter panel. Astrocytes also increased in the NAc following gestational stress exposure. Peripheral estradiol and progesterone concentrations were reduced in late pregnancy of stressed mothers, and at the transcript level, hormone receptor and synthesis molecules were altered in the NAc. Gestational stress also altered transcripts associated with synapses and synaptic plasticity during late pregnancy and the postpartum period. There was no impact of stress on engulfment of pre- and postsynaptic proteins by microglia. However, microglia engulfed more of the postsynaptic marker, PSD95, in late pregnancy relative to postpartum, indicating a potential role for microglia in remodeling synapses in the NAc. Overall, these studies provide novel evidence that gestational stress impacts endocrine, synaptic and neuroimmune factors in the maternal NAc, suggesting possible mechanisms by which stress during pregnancy contributes to peripartum mood disorders.

Postpartum depression (PPD) affects up to 20% of new mothers and has adverse consequences for the well-being of both mother and child. Exposure to stress during pregnancy as well as dysregulation in the mesolimbic dopamine (DA) reward system and its upstream modulator oxytocin (OT) have been independently linked to PPD. However, no studies have directly examined DA or OT signaling in the postpartum brain after gestational stress. Here we employed a chronic variable stress procedure during pregnancy and evaluated behavioral measures of mood and reward along with assessments of DA and OT signaling in postpartum rats. Our results show that gestational stress induced postpartum depressive-like and anxiety-like behavior in addition to producing reward-related deficits including anhedonia, impaired maternal care, and reduced maternal motivation. Consistent with a hypodopaminergic state, histological analysis revealed reduced expression of tyrosine hydroxylase in the NAc shell and core as well as reduced expression of the dopamine transporter and dopamine D2 receptor in the NAc shell of postpartum females exposed to gestational stress. A reduction in accumbal DA content as determined by liquid chromatography-mass spectrometry was also observed in gestationally-stressed dams. Lastly, we assessed mRNA expression of OT and OT receptors (OTR) and found that gestational stress increased OT expression in the hypothalamus but reduced OTR expression in the postpartum ventral tegmental area (VTA), a target of hypothalamic OT neurons. In the VTA, a reduction in OT-immunoreactive fibers following gestational stress was also seen. Taken together, these data demonstrate that the DA and OT systems within the postpartum reward circuit are sensitive to gestational stress and suggest that mood and maternal disruptions in PPD may arise from dysfunctional oxytocinergic regulation of the dopaminergic reward system.

Hormonal contraceptives (HCs) are one of the most highly prescribed classes of drugs in the world used for both contraceptive and noncontraceptive purposes. Despite their prevalent use, the impact of HCs on the brain remains inadequately explored. This review synthesizes recent findings on the neuroscience of HCs, with a focus on human structural neuroimaging as well as translational, nonhuman animal studies investigating the cellular, molecular, and behavioral effects of HCs. Additionally, we consider data linking HCs to mood disorders and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and stress response as a potential mediator. The review also addresses the unique sensitivity of the adolescent brain to HCs, noting significant changes in brain structure and function when HCs are used during this developmental period. Finally, we discuss potential effects of HCs in combination with smoking-derived nicotine on outcomes of ischemic brain damage. Methodological challenges, such as the variability in HC formulations and user-specific factors, are acknowledged, emphasizing the need for precise and individualized research approaches. Overall, this review underscores the necessity for continued interdisciplinary research to elucidate the neurobiological mechanisms of HCs, aiming to optimize their use and improve women's health.

is associated with profound acute and long-term physiological changes, but the effects of such changes on brain injury outcomes are unclear. Here, we examined the effects of previous pregnancy and maternal experience (parity) on acute neuroinflammatory responses to lateral fluid percussion injury (FPI), a well-defined experimental traumatic brain injury (TBI) paradigm. Multiparous (2-3 pregnancies and motherhood experiences) and age-matched nulliparous (no previous pregnancy or motherhood experience) female mice received either FPI or sham injury and were euthanized 3 days post-injury (DPI). Increased cortical Iba1, GFAP, and CD68 immunolabeling was observed following TBI independent of parity and microglia morphology did not differ between TBI groups. However, multiparous females had fewer CD45+ cells near the site of injury com-pared to nulliparous females, which was associated with preserved aquaporin-4 polarization, suggesting that par -ity may influence leukocyte recruitment to the site of injury and maintenance of blood brain barrier permeability following TBI. Additionally, relative cortical Il6 gene expression following TBI was dependent on parity such that TBI increased Il6 expression in nulliparous, but not multiparous, mice. Together, this work suggests that repro-ductive history may influence acute neuroinflammatory outcomes following TBI in females.(c) 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

20% of new mothers experience Postpartum Depression (PPD). The mechanisms contributing to PPD aren't well understood, but stress during pregnancy increases risk. Microglia, the brain’s innate immune cells, undergo peripartum-related changes within regions (e.g., medial prefrontal cortex, mPFC) regulating behaviors disrupted in PPD including mood and maternal care. Pregnancy also induces widespread neuroplasticity, and because microglia have been linked to synaptic remodeling, aberrant microglia-mediated synaptic remodeling may contribute to PPD.

Background: Basic research and clinical trials universally demonstrate the benefits of exercise for cognitive function.In recent studies, we determined that a period of initial exercise also creates and maintains a molecular memory window for exercise benefits on cognitive function in male and female mice where a brief, 2-day exercise session following a break can also re-engage cognitive benefits, re-facilitate long-term potentiation, and allow for learning under insufficient, subthreshold training conditions.Here, we build on these exercise parameters to begin to define a mechanism responsible for maintaining cognitive benefits underlying this molecular memory window by initial exercise and driving long-term memory formation.Methods: We utilized RNA-sequencing to uncover genes in the dorsal hippocampus that are differentially expressed under conditions where exercise benefits are maintained throughout sedentary delay periods and enable the formation of long-term memory and synaptic plasticity.Specifically, adult male mice underwent 14 days of initial exercise, received a sedentary delay period (0-2 weeks), and a brief 2-day period of reactivating exercise, followed by 3 min inadequate, subthreshold training in an object location memory (OLM) task and hippocampus was dissected during the consolidation window, 1 hour after training.Those parameters were then used to examine hippocampal longterm potentiation (LTP) using theta burst stimulation in the schaffer collateral pathway.To assess how exercise modulates epigenetic regulation of genes up-regulated only under conditions where exercise enabled the formation of long-term memory and synaptic plasticity, histone modifications were examined at Acvr1c and Bdnf IV promoters using chromatin immunoprecipitation (ChIP-qPCR).To examine the role of Acvr1c, a gene coding for a type 1 activin A membrane receptor kinase of the TGF-β family of signaling molecules, in hippocampus-dependent long term memory formation and synaptic plasticity, we used intrahippocampal delivery of AAV1-ACVR1C point mutant constructs that either enhance or disrupt function.Next, sedentary mice were trained using either a subthreshold (3 min) or standard (10 min) OLM task and memory was tested the following day.The same mice from behavioral studies were used to assess the impact of Acvr1c manipulation on hippocampal LTP.Given misregulation of the TGF-β pathway that occurs with age and in AD patients, we examine whether Acvr1c declines with age in mouse and human hippocampus (Genotype-Tissue Expression Project).Dorsal hippocampus was obtained from 3 and 20 mo.female and male C57BL/6J mice and processed for RT-qPCR.Additionally, Acvr1c transcripts per million (TPM) values from RNA-Seq data set obtained through the MODEL-AD consortium were analyzed from 4, 8 and 12 mo.C57BL/6J and 5xFAD female and male mice.We next aimed to determine whether enhancing ACVR1C through virus-mediated overexpression of wildtype ACVR1C would regulate long-term memory formation and synaptic plasticity in aging 18 mo.and 12 and 18 mo.Alzheimer's Disease (AD) mouse hippocampus and ameliorate impairments.Results: We demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory (Group: (F(6,64) = 8.13, P < 0.0001; Tukey test: P < 0.001, 14D vs. Sed) and synaptic plasticity (Group: (F(6,89) = 22.22,P < 0.0001; Tukey test: P < 0.0001) in adult mice compared to sedentary, effects which can be maintained and re-engaged with brief 2-day re-introduction to exercise following a sedentary delay (Behavior: Tukey test: P < 0.05, LTP: P < 0.0001, 2-day re-introduction vs sedentary).We identify a small number of genes whose expression correlate with conditions in which exercise facilitates long-term memory formation.Among these genes we found Acvr1c and Bdnf.We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c (Group (F(5,49) = 9.377, P < 0.0001) and Bdnf IV (Group (F(5,53) = 13.90,P < 0.0001) promoters during consolidation in a persistent manner, providing initial insight for maintenance of exercise benefits on long term memory.Disrupted ACVR1C function under adequate learning conditions in adults impairs memory (t(17) = 4.65, P = 0.0002) and synaptic plasticity (t(18) = 3.512, P = 0.0025).Conversely, overexpression of ACVR1C enables learning under inadequate training conditions in adults (t(18) = 3.303, P = 0.004) and enhances LTP (t(14) = 3.953, P = 0.0014).Furthermore, Acvr1c expression is impaired in the aging human (t(91) = 6.64,P = 0.0001), mouse (t(26) = 2.72, P = 0.01) and AD mouse brain (5xFAD) (Age: (F(2,48) = 54.95,P < 0.0001), and over-expression of Acvr1c ameliorates plasticity www.nature.com/npp1234567890();,:and cognitive impairment in aging (18 mo.C57: Behavior: (t(12) = 2.350, P = 0.036), LTP: (t(14) = 3.953, P = 0.001), 12 mo.5xFAD: Behavior: (t(21) = 2.287, P = 0.032), LTP: (t(16) = 5.617, P < 0.0001), 18 mo.5xFAD: LTP: (t(10) = 9.653, P = 0.001)).Conclusions: Together, these findings provide a new paradigm for uncovering mechanistic drivers of exercise-facilitated learning and provide opportunity to explore how specific exercise parameters allow for periods of maintained epigenetic and molecular changes through sedentary periods that facilitate cognitive function.As we have demonstrated here, identification of such mechanisms may extend beyond the context of exercise and aid in ameliorating age and AD-associated cognitive impairment.

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.

We are witnessing a stark increase in scientific interest in the neurobiological processes associated with pregnancy and maternity. Convergent evidence suggests that around the time of labour, first-time mothers experience a specific pattern of neuroanatomical changes that are associated with maternal behaviour. Here we provide an overview of the human neurobiological adaptations of motherhood, focusing on the interplay between pregnancy-related steroid and peptide hormones, and neuroplasticity in the brain. We discuss which brain plasticity mechanisms might underlie the structural changes detected by MRI, which hormonal systems are likely to contribute to such neuroanatomical changes and how these brain mechanisms may be linked to maternal behaviour. This Review offers an overarching framework that can serve as a roadmap for future investigations.

The female lifespan is marked by periods of dramatic hormonal fluctuation. Changes in the ovarian hormones estradiol and progesterone, in addition to the progesterone metabolite allopregnanolone, are among the most significant and have been shown to have widespread effects on the brain. This review summarizes current understanding of alterations that occur within the GABA system during the major hormonal transition periods of puberty, the ovarian cycle, pregnancy and the postpartum period, as well as reproductive aging. The functional impacts of altered inhibitory activity during these times are also discussed. Lastly, avenues for future research are identified, which, if pursued, can broaden understanding of the GABA system in the female brain and potentially lead to better treatments for women experiencing changes in brain function at each of these hormonal transition periods.

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.

PAWLUSKI, J.L., Hoekzema, E., Leuner, B., and Lonstein, J.S. Less can be more: Fine tuning the maternal brain. NEUROSCI BIOBEHAV REV (129) XXX-XXX, 2022. Plasticity in the female brain across the lifespan has recently become a growing field of scientific inquiry. This has led to the understanding that the transition to motherhood is marked by some of the most significant changes in brain plasticity in the adult female brain. Perhaps unexpectedly, plasticity occurring in the maternal brain often involves a decrease in brain volume, neurogenesis and glial cell density that presumably optimizes caregiving and other postpartum behaviors. This review summarizes what we know of the ‘fine-tuning’ of the female brain that accompanies motherhood and highlights the implications of these changes for maternal neurobehavioral health. The first part of the review summarizes structural and functional brain changes in humans during pregnancy and postpartum period with the remainder of the review focusing on neural and glial plasticity during the peripartum period in animal models. The aim of this review is to provide a clear understanding of when ‘less is more’ in maternal brain plasticity and where future research can focus to improve our understanding of the unique brain plasticity occurring during matrescence.