Region-specific Manner Research Articles

Motor learning promotes regionally-specific spindle-slow wave coupled cerebral memory reactivation.

Sleep is essential for the optimal consolidation of newly acquired memories. This study examines the neurophysiological processes underlying memory consolidation during sleep, via reactivation. Here, we investigated the impact of slow wave - spindle (SW-SP) coupling on regionally-task-specific brain reactivations following motor sequence learning. Utilizing simultaneous EEG-fMRI during sleep, our findings revealed that memory reactivation occured time-locked to coupled SW-SP complexes, and specifically in areas critical for motor sequence learning. Notably, these reactivations were confined to the hemisphere actively involved in learning the task. This regional specificity highlights a precise and targeted neural mechanism, underscoring the crucial role of SW-SP coupling. In addition, we observed double-dissociation whereby primary sensory areas were recruited time-locked to uncoupled spindles; suggesting a role for uncoupled spindles in sleep maintenance. These findings advance our understanding the functional significance of SW-SP coupling for enhancing memory in a regionally-specific manner, that is functionally dissociable from uncoupled spindles.

“Neuroinflammation”: does it have a role in chronic pain? Evidence from human imaging

Abstract Despite hundreds of studies demonstrating the involvement of neuron-glia-immune interactions in the establishment and/or maintenance of persistent pain behaviors in animals, the role (or even occurrence) of so-called “neuroinflammation” in human pain has been an object of contention for decades. Here, I present the results of multiple positron emission tomography (PET) studies measuring the levels of the 18 kDa translocator protein (TSPO), a putative neuroimmune marker, in individuals with various pain conditions. Overall, these studies suggest that brain TSPO PET signal: (1) is elevated, compared to healthy volunteers, in individuals with chronic low back pain (with additional elevations in spinal cord and neuroforamina), fibromyalgia, migraine and other conditions characterized by persistent pain; (2) has a spatial distribution exhibiting a degree of disorder specificity; (3) is parametrically linked to pain characteristics or comorbid symptoms (eg, nociplastic pain, fatigue, depression), as well as measures of brain function (ie, functional connectivity), in a regionally-specific manner. In this narrative, I also discuss important caveats to consider in the interpretation of this work (eg, regarding the cellular source of the signal and the complexities inherent in its acquisition and analysis). While the biological and clinical significance of these findings awaits further work, this emerging preclinical literature supports a role of neuron-glia-immune interactions as possible pathophysiological underpinnings of human chronic pain. Gaining a deeper understanding of the role of neuroimmune function in human pain would likely have important practical implications, possibly paving the way for novel interventions.

Olfactory and trigeminal routes of HSV-1 CNS infection with regional microglial heterogeneity.

Herpes simplex virus type 1 (HSV-1) primarily targets the oral and nasal epithelia before establishing latency in the trigeminal ganglion (TG) and other peripheral ganglia. HSV-1 can also infect and become latent in the central nervous system (CNS) independent of latency in the TGs. Recent studies suggest entry to the CNS via two distinct routes: the TG-brainstem connection and olfactory nerve; however, to date, there is no characterization of brain regions targeted during HSV-1 primary infection. Furthermore, the immune response by microglia may also contribute to the heterogeneity between different brain regions. However, the response to HSV-1 by microglia has not been characterized in a region-specific manner. This study investigated the time course of HSV-1 spread within the olfactory epithelium (OE) and CNS following intranasal inoculation and the corresponding macrophage/microglial response in a C57BL/6 mouse model. We found an apical to basal spread of HSV-1 within the OE and underlying tissue accompanied by an inflammatory response of macrophages. OE infection was followed by infection of a small subset of brain regions targeted by the TG in the brainstem and other cranial nerve nuclei, including the vagus and hypoglossal nerve. Furthermore, other brain regions were positive for HSV-1 antigens, such as the locus coeruleus (LC), raphe nucleus (RaN), and hypothalamus while sparing the hippocampus and cortex. Within each brain region, microglia activation also varied widely. These findings provide critical insights into the region-specific dissemination of HSV-1 within the CNS, elucidating potential mechanisms linking viral infection to neurological and neurodegenerative diseases.IMPORTANCEThis study shows how herpes simplex virus type 1 (HSV-1) spreads within the brain after infecting the nasal passages. Our data reveal the distinct pattern of HSV-1 through the brain during a non-encephalitic infection. Furthermore, microglial activation was also temporally and spatially specific, with some regions of the brain having sustained microglial activation even in the absence of viral antigens. Previous reports have identified specific brain regions found to be positive for HSV-1 infection; however, to date, there has not been a concise investigation of the anatomical spread of HSV-1 and the brain regions consistently vulnerable to viral entry and spread. Understanding these region-specific differences in infection and immune response is crucial because it links HSV-1 infection to potential triggers for neurological and neurodegenerative diseases.

Aging affects the mouse brain in a region-specific manner.

Aging-related cognitive decline is emerging as a health concern during the aging process of the global population. Hahn and colleagues found that glial aging was particularly accelerated in white matter compared to cortical regions. Specialized neuronal populations showed region-specific changes in gene expression. Acute dietary restriction triggers a reprogramming of genes associated with the circadian clock in glial cells, whereas injections of young mouse plasma selectively reverse age-related expression patterns. The discovery of region-specific aging could enhance our understanding of the aging process and offer new possibilities for innovative treatment strategies and interventions for cognitive impairments related to aging.

Deciphering mouse brain spatial diversity via glyco-lipidomic mapping

Gangliosides in the brain play a crucial role in modulating the integrity of vertebrate central nervous system in a region-specific manner. However, to date, a comprehensive structural elucidation of complex intact ganglioside isomers has not been achieved, resulting in the elusiveness into related molecular mechanism. Here, we present a glycolipidomic approach for isomer-specific and brain region-specific profiling of the mouse brain. Considerable region-specificity and commonality in specific group of regions are highlighted. Notably, we observe a similarity in the abundance of major isomers, GD1a and GD1b, within certain regions, which provides significant biological implications with interpretation through the lens of a theoretical retrosynthetic state-transition network. Furthermore, A glycocentric-omics approaches using gangliosides and N-glycans reveal a remarkable convergence in spatial dynamics, providing valuable insight into molecular interaction network. Collectively, this study uncovers the spatial dynamics of intact glyco-conjugates in the brain, which are relevant to regional function and accelerates the discovery of potential therapeutic targets for brain diseases.

Effects of prenatal cocaine exposure on estrous cycle, and behavior and expression of estrogen receptor alpha and oxytocin during estrus and diestrus in mice offspring.

Increasing evidence indicates that prenatal cocaine exposure may result in many developmental and long-lasting neurological and behavioral effects. The behaviors of female animals are strongly associated with the estrous cycle. Estrogen receptors and oxytocin are important neuroendocrine factors that regulate social behavior and are of special relevance to females. However, whether prenatal cocaine exposure induces estrous cycle changes in offspring and whether neurobehavioral changes in estrus and diestrus offspring differ remains unclear. On gestational day 12, mice were administered cocaine once daily for seven consecutive days, then the estrous cycle was examined in adult female offspring, as well as locomotion, anxiety level, and social behaviors, and the expression of estrogen receptor alpha-immunoreactive and oxytocin-immunoreactive neurons were compared between estrus and diestrus offspring. Prenatal cocaine exposure resulted in the shortening of proestrus and estrus in the offspring. During estrus and diestrus, prenatally cocaine-exposed offspring showed increased anxiety levels and changed partial social behaviors; their motility showed no significant differences in estrus, but declined in diestrus. Prenatal cocaine exposure reduced estrogen receptor alpha-immunoreactive expression in the medial preoptic area, ventromedial hypothalamic nucleus, and arcuate nucleus and oxytocin-immunoreactive expression in the paraventricular nucleus in estrus and diestrus offspring. These results suggest that prenatal cocaine exposure induces changes in the offspring's estrous cycle and expression of estrogen receptor alpha and oxytocin in a brain region-specific manner and that prenatal cocaine exposure and the estrous cycle interactively change motility and partial social behavior. Estrogen receptor alpha and oxytocin signaling are likely to play important concerted roles in mediating the effects of prenatal cocaine exposure on the offspring.

Toxoplasma gondii Infection of Alzheimer's Disease Mice Reduces Brain Amyloid Density Globally and Regionally.

Toxoplasma gondii infection of Alzheimer's disease model mice decreases amyloid β plaques. We aimed to determine if there is a brain regional difference in amyloid β reduction in the brains of T. gondii-infected compared to control mice. Three-month-old 5xFAD (AD model) mice were injected with T. gondii or with phosphate-buffered saline as a control. Intact brains were harvested at 6 weeks postinfection, optically cleared using iDISCO+, and brain-wide amyloid burden was visualized using volumetric light-sheet imaging. Amyloid signal was quantified across each brain and computationally mapped to the Allen Institute Brain Reference Atlas to determine amyloid density in each region. A brain-wide analysis of amyloid in control and T. gondii-infected 5xFAD mice revealed that T. gondii infection decreased amyloid burden in the brain globally as well as in the cortex and hippocampus, and many daughter regions. Daughter regions that showed reduced amyloid burden included the prelimbic cortex, visual cortex, and retrosplenial cortex. The olfactory tubercle, a region known to have increased monocytes following T. gondii infection, also showed reduced amyloid after infection. T. gondii infection of AD mice reduces amyloid burden in a brain region-specific manner that overlaps with known regions of T. gondii infection and peripheral immune cell infiltration.

Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models.

Region-specific synapse loss is an early pathological hallmark in Alzheimer's disease (AD). Emerging data in mice and humans highlight microglia, the brain-resident macrophages, as cellular mediators of synapse loss; however, the upstream modulators of microglia-synapse engulfment remain elusive. Here, we report a distinct subset of astrocytes, which are glial cells essential for maintaining synapse homeostasis, appearing in a region-specific manner with age and amyloidosis at onset of synapse loss. These astrocytes are distinguished by their peri-synaptic processes which are 'bulbous' in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integrated in vitro and in vivo approaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking down Mfge8 specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.

Spatial transcriptome reveals the region-specific genes and pathways regulated by Satb2 in neocortical development

BackgroundIt is known that the neurodevelopmental disorder associated gene, Satb2, plays important roles in determining the upper layer neuron specification. However, it is not well known how this gene regulates other neocortical regions during the development. It is also lack of comprehensive delineation of its spatially regulatory pathways in neocortical development.ResultsIn this work, we utilized spatial transcriptomics and immuno-staining to systematically investigate the region-specific gene regulation of Satb2 by comparing the Satb2+/+ and Satb2−/− mice at embryonic stages, including the ventricle zone (VZ) or subventricle zone (SVZ), intermediate zone (IZ) and cortical plate (CP) respectively. The staining result reveals that these three regions become moderately or significantly thinner in the Satb2−/− mice. In the cellular level, the cell number increases in the VZ/SVZ, whereas the cell number decreases in the CP. The spatial transcriptomics data show that many important genes and relevant pathways are dysregulated in Satb2−/− mice in a region-specific manner. In the VZ/SVZ, the key genes involved in neural precursor cell proliferation, including the intermediate progenitor marker Tbr2 and the lactate production related gene Ldha, are up-regulated in Satb2−/− mice. In the IZ, the key genes in regulating neuronal differentiation and migration, such as Rnd2, exhibit ectopic expressions in the Satb2−/− mice. In the CP, the lineage-specific genes, Tbr1 and Bcl11b, are abnormally expressed. The neuropeptide related gene Npy is down-regulated in Satb2−/− mice. Finally, we validated the abnormal expressions of key regulators by using immunofluorescence or qPCR.ConclusionsIn summary, our work provides insights on the region-specific genes and pathways which are regulated by Satb2 in neocortical development.

Prenatal Exposure to Bisphenol A and/or Diethylhexyl Phthalate Impacts Brain Monoamine Levels in Rat Offspring.

This study examines the sex-specific effects of gestational exposure (days 6-21) to endocrine-disrupting chemicals such as bisphenol A (BPA), diethylhexyl phthalate (DEHP), or their combination on brain monoamine levels that play an important role in regulating behavior. Pregnant Sprague-Dawley rats were orally administered saline, low doses (5 µg/kg BW/day) of BPA or DEHP, and their combination or a high dose (7.5 mg/kg BW/day) of DEHP alone or in combination with BPA during pregnancy. The offspring were subjected to a behavioral test and sacrificed in adulthood, and the brains were analyzed for neurotransmitter levels. In the paraventricular nucleus, there was a marked reduction in dopamine levels (p < 0.01) in male offspring from the BPA, DEHP, and B + D (HD) groups, which correlated well with their shock probe defensive burying times. Neurotransmitter changes in all brain regions examined were significant in female offspring, with DEHP (HD) females being affected the most, followed by the B + D groups. BPA and/or DEHP (LD) increased monoamine turnover in a region-specific manner in male offspring (p < 0.05). Overall, prenatal exposure to BPA, DEHP, or their combination alters monoamine levels in a brain region-specific, sex-specific, and dose-dependent manner, which could have implications for their behavioral and neuroendocrine effects.

Estrogen receptor beta signaling enhances extinction memory recall for heroin-conditioned cues in a sex- and region-specific manner

Return to use, or relapse, is a major challenge in the treatment of opioid use disorder (OUD). Relapse can be precipitated by several factors, including exposure to drug-conditioned cues. Identifying successful treatments to mitigate cue-induced relapse has been challenging, perhaps due to extinction memory recall (EMR) deficits. Previously, inhibition of estradiol (E2) signaling in the basolateral amygdala (BLA) impaired heroin-cue EMR. This effect was recapitulated by antagonism of BLA estrogen receptors (ER) in a sex-specific manner such that blocking ERα in males, but ERβ in females, impaired EMR. However, it is unclear whether increased E2 signaling, in the BLA or systemically, enhances heroin-cue EMR. We hypothesized that ERβ agonism would enhance heroin-cue EMR in a sex- and region-specific manner. To determine the capacity of E2 signaling to improve EMR, we pharmacologically manipulated ERβ across several translationally designed experiments. First, male and female rats acquired heroin or sucrose self-administration. Next, during a cued extinction session, we administered diarylpropionitrile (DPN, an ERβ agonist) and tested anxiety-like behavior on an open field. Subsequently, we assessed EMR in a cue-induced reinstatement test and, finally, measured ERβ expression in several brain regions. Across all experiments, females took more heroin and sucrose than males and had greater responses during heroin-cued extinction. Administration of DPN in the BLA enhanced EMR in females only, driven by ERβ’s impacts on memory consolidation. Interestingly, however, systemic DPN administration improved EMR for heroin cues in both sexes across several different tests, but did not impact sucrose-cue EMR. Immunohistochemical analysis of ERβ expression across several different brain regions showed that females only had greater expression of ERβ in the basal nucleus of the BLA. Here, in several preclinical experiments, we demonstrated that ERβ agonism enhances heroin-cue EMR and has potential utility in combatting cue-induced relapse.

A discrete subpopulation of PFC-LHb neurons govern cocaine place preference

Addiction is a complex behavioral disorder characterized by compulsive drug-seeking and drug use despite harmful consequences. The prefrontal cortex (PFC) plays a crucial role in cocaine addiction, involving decision-making, impulse control, memory, and emotional regulation. The PFC interacts with the brain’s reward system, including the ventral tegmental area (VTA) and nucleus accumbens (NAc). The PFC also projects to the lateral habenula (LHb), a brain region critical for encoding negative reward and regulating the reward system. In the current study, we examined the role of PFC-LHb projections in regulating cocaine reward-related behaviors. We found that optogenetic stimulation of the PFC-LHb circuit during cocaine conditioning abolished cocaine preference without causing aversion. In addition, increased c-fos expression in LHb neurons was observed in animals that received optic stimulation during cocaine conditioning, supporting the circuit’s involvement in cocaine preference regulation. Molecular analysis in animals that received optic stimulation revealed that cocaine-induced alterations in the expression of GluA1 subunit of AMPA receptor was normalized to saline levels in a region-specific manner. Moreover, GluA1 serine phosphorylation on S845 and S831 were differentially altered in LHb and VTA but not in the PFC. Together these findings highlight the critical role of the PFC-LHb circuit in controlling cocaine reward-related behaviors and shed light on the underlying mechanisms. Understanding this circuit’s function may provide valuable insights into addiction and contribute to developing targeted treatments for substance use disorders.

Development of a High-Throughput Pipeline to Characterize Microglia Morphological States at a Single-Cell Resolution.

As rapid responders to their environments, microglia engage in functions that are mirrored by their cellular morphology. Microglia are classically thought to exhibit a ramified morphology under homeostatic conditions which switches to an ameboid form during inflammatory conditions. However, microglia display a wide spectrum of morphologies outside of this dichotomy, including rod-like, ramified, ameboid, and hypertrophic states, which have been observed across brain regions, neurodevelopmental timepoints, and various pathological contexts. We applied dimensionality reduction and clustering to consider contributions of multiple morphology measures together to define a spectrum of microglial morphological states in a mouse dataset that we used to demonstrate the utility of our toolset. Using ImageJ, we first developed a semiautomated approach to characterize 27 morphology features from hundreds to thousands of individual microglial cells in a brain region-specific manner. Within this pool of features, we defined distinct sets of highly correlated features that describe different aspects of morphology, including branch length, branching complexity, territory span, and circularity. When considered together, these sets of features drove different morphological clusters. Our tools captured morphological states similarly and robustly when applied to independent datasets and using different immunofluorescent markers for microglia. We have compiled our morphology analysis pipeline into an accessible, easy-to-use, and fully open-source ImageJ macro and R package that the neuroscience community can expand upon and directly apply to their own analyses. Outcomes from this work will supply the field with new tools to systematically evaluate the heterogeneity of microglia morphological states across various experimental models and research questions.

Estrogen deficiency reduces maximal running capacity and affects serotonin levels differently in the hippocampus and nucleus accumbens in response to acute exercise.

Estrogen deficiency is associated with unfavorable changes in body composition and metabolic health. While physical activity ameliorates several of the negative effects, loss of ovarian function is associated with decreased physical activity levels. It has been proposed that the changes in brain neurochemical levels and /or impaired skeletal muscle function may underlie this phenomenon. We studied the effect of estrogen deficiency induced via ovariectomy (OVX) in female Wistar rats (n = 64). Rats underwent either sham or OVX surgery and were allocated thereafter into four groups matched for body mass and maximal running capacity: sham/control, sham/max, OVX/control, and OVX/max, of which the max groups had maximal running test before euthanasia to induce acute response to exercise. Metabolism, spontaneous activity, and maximal running capacity were measured before (PRE) and after (POST) the surgeries. Three months following the surgery, rats were euthanized, and blood and tissue samples harvested. Proteins were analyzed from gastrocnemius muscle and retroperitoneal adipose tissue via Western blot. Brain neurochemical markers were measured from nucleus accumbens (NA) and hippocampus (HC) using ultra-high performance liquid chromatography. OVX had lower basal energy expenditure and higher body mass and retroperitoneal adipose tissue mass compared with sham group (p ≤ 0.005). OVX reduced maximal running capacity by 17% (p = 0.005) with no changes in muscle mass or phosphorylated form of regulatory light chain (pRLC) in gastrocnemius muscle. OVX was associated with lower serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) level in the NA compared with sham (p = 0.007). In response to acute exercise, OVX was associated with low serotonin level in the HC and high level in the NA (p ≤ 0.024). Our results highlight that OVX reduces maximal running capacity and affects the response of brain neurochemical levels to acute exercise in a brain region-specific manner. These results may offer mechanistic insight into why OVX reduces willingness to exercise.

A clathrin mediated endocytosis scaffolding protein, Intersectin 1, changes in an isoform, brain region, and sex specific manner in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary Tau tangles in the brain. We previously identified a set of candidate AD microRNAs (miRNAs) in human cerebrospinal fluid (CSF) and used a target prediction pipeline to identify mRNAs and pathways that could potentially be regulated by the miRNAs. Of these pathways, clathrin mediated endocytosis (CME) was selected for further investigation. CME is altered in multiple brain cell types in AD and is implicated in early cellular phenotypes such as enlarged early endosomes and pathogenic processing of Aβ. However, a comprehensive evaluation of major CME hub proteins in humans with AD across multiple brain regions is lacking. Thus, we used immunoblots to evaluate human post-mortem AD and control (CTL) frontal cortex (FC; AD n = 22, CTL n = 23) and hippocampus (HP; AD n = 34, CTL n = 22) for changes in Intersectin 1 (ITSN1), Phosphatidylinositol Binding Clathrin Assembly Protein gene (PICALM), Clathrin Light Chain (CLT), FCH and Mu Domain Containing Endocytic Adaptor 1 (FCHO1), Adaptor Related Protein Complex 2 (AP2) Subunit Alpha 1 (AP2A1), and Dynamin 2 (DNM2). Of these, we found that in AD, ITSN1-long (ITSN1-L) was decreased in the FC of males and HP of females, while ITSN1-short was increased in the HP of both males and females. We further evaluated ITSN1-L levels in cortex (CTX) and HP of the 5xFAD mouse model of Aβ pathology at different timepoints during aging and disease progression by immunoblot (n = 5-8 per group). At 3 months, female 5xFAD exhibited an increase of ITSN1-L in CTX but a decrease at 6 and 9 months. Additionally, immunofluorescent staining of 5xFAD primary HP neurons showed an increase of ITSN1-L in matured 5xFAD neurons at 21 and 28 days in vitro. Together, our studies show that in AD, isoforms of ITSN1 change in a brain region-and sex-dependent manner. Further, changes in ITSN1-L are transient with levels increasing during early Aβ accumulation and decreasing during later progression. These findings suggest that ITSN1 expression, and consequently CME activity, may change depending on the stage of disease progression.

Early Handling Exerts Anxiolytic Effects and Alters Brain Mitochondrial Dynamics in Adult High Anxiety Mice.

Early handling (EH), the brief separation of pups from their mother during early life, has been shown to exert beneficial effects. However, the impact of EH in a high anxiety background as well as the role of brain mitochondria in shaping EH-driven responses remain elusive.Here, we used a high (HAB) vs. normal (NAB) anxiety-related behavior mouse model to study how EH affects pup and dam behavior in divergent anxiety backgrounds. We also investigated EH-induced effects at the protein and mRNA levels in adult male HAB mice in the hypothalamus, the prefrontal cortex, and the hippocampus by examining the same mitochondrial/energy pathways and mitochondrial dynamics mechanisms (fission, fusion, biogenesis, and mitophagy) in all three brain regions.EH exerts anxiolytic effects in adult HAB but not NAB male mice and does not affect HAB or NAB maternal behavior, although basal HAB vs. NAB maternal behaviors differ. In adult HAB male mice, EH does not impact oxidative phosphorylation (OXPHOS) and oxidative stress in any of the brain regions studied but leads to increased protein expression of glycolysis enzymes and a correlation of anxiety-related behavior with Krebs cycle enzymes in HAB mice in the hypothalamus. Intriguingly, EH alters mitochondrial dynamics by increasing hypothalamic DRP1, OPA1, and PGC1a protein levels. At the mRNA level, we observe altered, EH-driven mitochondrial dynamics mRNA signatures which predominantly affect the prefrontal cortex.Taken together, our results show that EH exerts anxiolytic effects in adulthood in high anxiety and modulates mitochondrial dynamics pathways in a brain region-specific manner.

An Aggressive Interaction Rapidly Increases Brain Androgens in a Male Songbird during the Non-breeding Season.

Aggression is a crucial behavior that impacts access to limited resources in different environmental contexts. Androgens synthesized by the gonads promote aggression during the breeding season. However, aggression can be expressed during the non-breeding season, despite low androgen synthesis by the gonads. The brain can also synthesize steroids ("neurosteroids"), including androgens, which might promote aggression during the non-breeding season. Male song sparrows, Melospiza melodia, are territorial year-round and allow the study of seasonal changes in the steroid modulation of aggression. Here, we quantified steroids following a simulated territorial intrusion (STI) for 10 min in wild adult male song sparrows during the breeding and non-breeding seasons. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we examined 11 steroids: pregnenolone, progesterone, corticosterone, dehydroepiandrosterone, androstenedione, testosterone, 5α-dihydrotestosterone, 17β-estradiol, 17α-estradiol, estriol, and estrone. Steroids were measured in blood and 10 microdissected brain regions that regulate social behavior. In both seasons, STI increased corticosterone in the blood and brain. In the breeding season, STI had no rapid effects on androgens or estrogens. Intriguingly, in the non-breeding season, STI increased testosterone and androstenedione in several behaviorally relevant regions, but not in the blood, where androgens remained non-detectable. Also in the non-breeding season, STI increased progesterone in the blood and specific brain regions. Overall, rapid socially modulated changes in brain steroid levels are more prominent during the non-breeding season. Brain steroid levels vary with season and social context in a region-specific manner and suggest a role for neuroandrogens in aggression during the non-breeding season.

Altered excitatory and inhibitory ionotropic receptor subunit expression in the cortical visuospatial working memory network in schizophrenia.

Dysfunction of the cortical dorsal visual stream and visuospatial working memory (vsWM) network in individuals with schizophrenia (SZ) likely reflects alterations in both excitatory and inhibitory neurotransmission within nodes responsible for information transfer across the network, including primary visual (V1), visual association (V2), posterior parietal (PPC), and dorsolateral prefrontal (DLPFC) cortices. However, the expression patterns of ionotropic glutamatergic and GABAergic receptor subunits across these regions, and alterations of these patterns in SZ, have not been investigated. We quantified transcript levels of key subunits for excitatory N-methyl-D-aspartate receptors (NMDARs), excitatory alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs), and inhibitory GABAA receptors (GABAARs) in postmortem total gray matter from V1, V2, PPC, and DLPFC of unaffected comparison (UC) and matched SZ subjects. In UC subjects, levels of most AMPAR and NMDAR mRNAs exhibited opposite rostral-to-caudal gradients, with AMPAR GRIA1 and GRIA2 mRNA levels highest in DLPFC and NMDAR GRIN1 and GRIN2A mRNA levels highest in V1. GABRA5 and GABRA1 mRNA levels were highest in DLPFC and V1, respectively. In SZ, most transcript levels were lower relative to UC subjects, with these differences largest in V1, intermediate in V2 and PPC, and smallest in DLPFC. In UC subjects, these distinct patterns of receptor transcript levels across the cortical vsWM network suggest that the balance between excitation and inhibition is achieved in a region-specific manner. In SZ subjects, the large deficits in excitatory and inhibitory receptor transcript levels in caudal sensory regions suggest that abnormalities early in the vsWM pathway might contribute to altered information processing in rostral higher-order regions.

Obesity differentially effects the somatosensory cortex and striatum of TgF344-AD rats

Lifestyle choices leading to obesity, hypertension and diabetes in mid-life contribute directly to the risk of late-life Alzheimer’s disease (AD). However, in late-life or in late-stage AD conditions, obesity reduces the risk of AD and disease progression. To examine the mechanisms underlying this paradox, TgF344-AD rats were fed a varied high-carbohydrate, high-fat (HCHF) diet to induce obesity from nine months of age representing early stages of AD to twelve months of age in which rats exhibit the full spectrum of AD symptomology. We hypothesized regions primarily composed of gray matter, such as the somatosensory cortex (SSC), would be differentially affected compared to regions primarily composed of white matter, such as the striatum. We found increased myelin and oligodendrocytes in the somatosensory cortex of rats fed the HCHF diet with an absence of neuronal loss. We observed decreased inflammation in the somatosensory cortex despite increased AD pathology. Compared to the somatosensory cortex, the striatum had fewer changes. Overall, our results suggest that the interaction between diet and AD progression affects myelination in a brain region specific manner such that regions with a lower density of white matter are preferentially affected. Our results offer a possible mechanistic explanation for the obesity paradox.

Social isolation postweaning alters reward-related dopamine dynamics in a region-specific manner in adolescent male rats

Early development is characterized by dynamic transitions in brain maturation, which may be impacted by environmental factors. Here, we sought to determine the effects of social isolation from postweaning and during adolescence on reward behavior and dopaminergic signaling in male rats. Subjects were socially isolated or group housed at postnatal day 21. Three weeks later, extracellular dopamine concentrations were examined in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAc) during a feeding bout. Surprisingly, opposing effects were found in which increased mPFC dopamine concentrations were observed in group housed, but not isolated, rats. In stark contrast, increased dopamine levels were found in the NAc of isolated, but not group housed, rats. Moreover, the absence of an effect in the mPFC of the isolated rats could not be reversed by subsequent group housing, demonstrating the remarkable long-term effects on dopamine signaling dynamics. When provided a highly palatable food, the isolated subjects exhibited a dramatic increase in mPFC dopamine levels when the chocolate was novel, but no effects following chronic chocolate consumption. In contrast, the group housed subjects showed significantly increased dopamine levels only with chronic chocolate consumption. The dopamine changes were correlated with differences in behavioral measures. Importantly, the deficit in reward-related behavior during isolation could be reversed by microinjection of either dopamine or cocaine into the mPFC. Together, these data provide evidence that social isolation from postweaning and during adolescence alters reward-induced dopamine levels in a brain region-specific manner, which has important functional implications for reward-related behavior.