Limbic Brain Regions Research Articles

Synchronized LFP rhythmicity in the social brain reflects the context of social encounters

Mammalian social behavior is highly context-sensitive. Yet, little is known about the mechanisms that modulate social behavior according to its context. Recent studies have revealed a network of mostly limbic brain regions which regulates social behavior. We hypothesize that coherent theta and gamma rhythms reflect the organization of this network into functional sub-networks in a context-dependent manner. To test this concept, we simultaneously record local field potential (LFP) from multiple social brain regions in adult male mice performing three social discrimination tasks. While LFP rhythmicity across all tasks is dominated by a global internal state, the pattern of theta coherence between the various regions reflect the behavioral task more than other variables. Moreover, Granger causality analysis implicate the ventral dentate gyrus as a main player in coordinating the context-specific rhythmic activity. Thus, our results suggest that the pattern of coordinated rhythmic activity within the network reflects the subject’s social context.

Post-weaning social isolation alters sociability in a sex-specific manner.

Adolescence is a critical period for brain development in humans and stress exposure during this time can have lasting effects on behavior and brain development. Social isolation and loneliness are particularly salient stressors that lead to detrimental mental health outcomes particularly in females, although most of the preclinical work on social isolation has been done in male animals. Our lab has developed a model of post-weaning adolescent social isolation that leads to increased drug reward sensitivity and altered neuronal structure in limbic brain regions. The current study utilized this model to determine the impact of adolescent social isolation on a three-chamber social interaction task both during adolescence and adulthood. We found that while post-weaning isolation does not alter social interaction during adolescence (PND45), it has sex-specific effects on social interaction in young adulthood (PND60), potentiating social interaction in male mice and decreasing it in female mice. As early life stress can activate microglia leading to alterations in neuronal pruning, we next examined the impact of inhibiting microglial activation with daily minocycline administration during the first 3 weeks of social isolation on these changes in social interaction. During adolescence, minocycline dampened social interaction in male mice, while having no effect in females. In contrast, during young adulthood, minocycline did not alter the impact of adolescent social isolation in males, with socially isolated males exhibiting higher levels of social interaction compared to their group housed counterparts. In females, adolescent minocycline treatment reversed the effect of social isolation leading to increased social interaction in the social isolation group, mimicking what is seen in naïve males. Taken together, adolescent social isolation leads to sex-specific effects on social interaction in young adulthood and adolescent minocycline treatment alters the effects of social isolation in females, but not males.

Reduced serotonergic transmission alters sensitivity to cost and reward via 5-HT1A and 5-HT1B receptors in monkeys.

Serotonin (5-HT) deficiency is a core biological pathology underlying depression and other psychiatric disorders whose key symptoms include decreased motivation. However, the exact role of 5-HT in motivation remains controversial and elusive. Here, we pharmacologically manipulated the 5-HT system in macaque monkeys and quantified the effects on motivation for goal-directed actions in terms of incentives and costs. Reversible inhibition of 5-HT synthesis increased errors and reaction times on goal-directed tasks, indicating reduced motivation. Analysis found incentive-dependent and cost-dependent components of this reduction. To identify the receptor subtypes that mediate cost and incentive, we systemically administered antagonists specific to 4 major 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4. Positron emission tomography (PET) visualized the unique distribution of each subtype in limbic brain regions and determined the systemic dosage for antagonists that would achieve approximately 30% occupancy. Only blockade of 5-HT1A decreased motivation through changes in both expected cost and incentive; sensitivity to future workload and time delay to reward increased (cost) and reward value decreased (incentive). Blocking the 5-HT1B receptor also reduced motivation through decreased incentive, although it did not affect expected cost. These results suggest that 5-HT deficiency disrupts 2 processes, the subjective valuation of costs and rewards, via 5-HT1A and 5-HT1B receptors, thus leading to reduced motivation.

Potential Link Between Exercise and N-Methyl-D-Aspartate Glutamate Receptors in Alcohol Use Disorder: Implications for Therapeutic Strategies.

Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.

Novel hippocampal genes involved in enhanced susceptibility to chronic pain-induced behavioral emotionality

Altered mood and psychiatric disorders are commonly associated with chronic pain conditions; however, brain mechanisms linking pain and comorbid clinical depression are still largely unknown. In this study, we aimed to identify whether key genes/cellular mechanisms underlie susceptibility/resiliency to development of depressive-like behaviors during chronic pain state. Genome-wide RNA-seq analysis was used to examine the transcriptomic profile of the hippocampus, a limbic brain region that regulates mood and stress responses, from male rats exposed to chronic inflammatory pain. Pain-exposed animals were separated into either ‘resilient’ or ‘susceptible’ to development of enhanced behavioral emotionality based on behavioral testing. RNA-seq bioinformatic analysis, followed by validation using qPCR, revealed dysregulation of hippocampal genes involved in neuroinflammation, cell cycle/neurogenesis and blood-brain barrier integrity. Specifically, ADAM Metallopeptidase Domain 8 (Adam8) and Aurora Kinase B (Aurkb), genes with functional roles in activation of the NLRP3 inflammasome and microgliosis, respectively, were significantly upregulated in the hippocampus of ‘susceptible’ animals expressing increased behavioral emotionality. In addition, genes associated with blood-brain barrier integrity, such as the Claudin 4 (Cldn4), a tight junction protein and a known marker of astrocyte activation, were also significantly dysregulated between ‘resilient’ or ‘susceptible’ pain groups. Furthermore, differentially expressed genes (DEGs) were further characterized in rodents stress models to determine whether their hippocampal dysregulation is driven by common stress responses vs. affective pain processing. Altogether these results continue to strengthen the connection between dysregulation of hippocampal genes involved in neuroinflammatory and neurodegenerative processes with increased behavioral emotionality often expressed in chronic pain state

Digital pathology analysis reveals TDP‐43 pathology as a strong predictor of glial activation in Alzheimer’s disease

AbstractBackgroundGlial activation plays a critical role in Alzheimer’s disease (AD) pathogenesis and is associated with amyloid‐β plaques and neurofibrillary tangles composed of phosphorylated tau (phospho‐tau). With approximately 40%‐60% of AD cases having limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), TDP‐43 pathology has become more the rule than the exception in AD brains. However, the effect of LATE‐NC in AD‐related glial activation is unknown.MethodWe analyzed the effect of TDP‐43 pathology on glial activation in three AD subtypes: hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. Twenty cases of each subtype (n = 60 total) were selected from the FLorida Autopsied Multi‐Ethnic (FLAME) cohort. Cases were immunohistochemically evaluated on serial sections of the hippocampus in the CA1 and subiculum subsectors, and superior temporal, inferior parietal, and mid‐frontal cortices with antibodies to CD68 (phagocytosis), GFAP (astrogliosis), GT‐38 (conformation‐specific AD‐type tau), 6F/3D (amyloid‐β), and phospho‐Serine 409/410 of TDP‐43 (pTDP‐43). Digital pathology was employed to quantify immunohistochemical staining. Multivariable regression modeling was utilized to understand the relationship between glial activation and AD pathologies.ResultThe level of glial activation, defined as % of immunoreactive surface area for CD68 and GFAP, was lowest in HpSp AD (0.54%, 13%), whereas typical AD (1.3%, 33%) and limbic predominant AD (1.3%, 30%) had similar levels suggesting a ceiling effect, or plateau, of gliosis levels (both p<0.001). HpSp AD was more often male (p<0.001) and younger at disease onset (p<0.001) compared to both typical AD and limbic predominant AD. Multivariable regression modeling of CD68 (subiculum R2 = 0.60) identified advanced tau to be a significant predictor of CD68 in all brain regions. LATE‐NC stage predicted increased CD68 levels in limbic brain regions. Multivariable regression modeling of GFAP (CA1 R2 = 0.60) showed that Aβ was the strongest predictor of astrogliosis in CA1 and subiculum (p<0.001). Advanced tau in CA1 and parietal cortex, LATE‐NC in subiculum and temporal cortex, and APOE4 genotype in CA1 predicted a significant increase in GFAP.ConclusionThese findings highlight the significant role TDP‐43 pathology plays in affecting the microenvironment and interplay between neuroinflammation and neurodegeneration and have important implications for therapeutic strategies in AD with co‐morbid LATE‐NC.

A Scoping Review of Potential Biological Mechanisms and Predictors of Interpersonal Psychotherapy

Social dysfunction plays a critical role in the development and maintenance of depression in both adolescents and adults. Interpersonal psychotherapy (IPT) and interpersonal psychotherapy for depressed adolescents (IPT-A) are effective, evidence-based, and time-limited treatments for depression that aim to mitigate depressive symptoms by strengthening an individual’s interpersonal relationships and skills. Though the efficacy of IPT/IPT-A has been well established, we are just beginning to know how biological systems are implicated in its success. In this scoping review, we examine the extant literature on biological mechanisms and predictors of IPT/IPT-A treatment efficacy. Overall, seven studies were identified that consider biological processes in the context of evaluating IPT/IPTA, and the studies that were conducted are typically preliminary in nature. Notably, there is some evidence showing that the hypothalamic–pituitary–adrenal axis, various frontal and limbic brain regions, and behavioral indexes that represent brain functioning are associated with changes in IPT/IPT-A or predictive of IPT/IPT-A outcomes. We also consider consequences for treatment and future research. The hope is that a better understanding of how and for whom IPT/IPT-A works can optimize the success of the treatment in reducing an individual’s depressive symptoms.

Downregulation of the GABAA receptor β2 subunit in a rat model of autism

Introduction: Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain, and GABA type A receptor (GABAA) activation mediates fast inhibitory actions. Numerous studies have shown that individual with autism spectrum disorder (ASD) exhibit abnormalities in the expression of GABAA receptors in various brain areas. Additionally, animal models of ASD have suggested alterations in GABAergic neurotransmission and a dysregulation in the balance between inhibitory and excitatory systems. Objective: We investigated the immunolabeling of the GABAA receptor β2 subunit (GARB2) in the hippocampus, the amygdala, and thalamus of infant rats prenatally exposed to valproic acid (VPA) as an ASD model. Methods: Pregnant females were injected with VPA (600mg/Kg, i.p.) during the twelfth embryonic day; control rats were injected with saline. On the fourteen-postnatal-day, rats from both experimental groups were anesthetized, transcardially perfused with 0.9% NaCl and 4% paraformaldehyde, and sequential coronal brain sections (40μm thickness) were obtained. Immunohistochemistry was performed to detect GARB2 and the relative optical density (OD) of expression was analyzed. Results: Our data showed a statistically significant downregulation of GARB2 in the lateral amygdaloid nucleus, as well as in the ventral and lateral thalamic nuclei when compared to control rats. No statistically significant differences were detected in the hippocampus. Discussion: Our findings suggest that prenatal exposure to VPA reduces GARB2 expression in limbic brain regions involved in social-emotional behaviors, like previous reports in individuals with ASD. Conclusion These results support for the involvement of the GABAergic system in the pathogenesis of ASD.

Neuroimaging in Adolescents: Post-Traumatic Stress Disorder and Risk for Substance Use Disorders.

Trauma in childhood and adolescence has long-term negative consequences in brain development and behavior and increases the risk for psychiatric disorders. Among them, post-traumatic stress disorder (PTSD) during adolescence illustrates the connection between trauma and substance misuse, as adolescents may utilize substances to cope with PTSD. Drug misuse may in turn lead to neuroadaptations in learning processes that facilitate the consolidation of traumatic memories that perpetuate PTSD. This reflects, apart from common genetic and epigenetic modifications, overlapping neurocircuitry engagement triggered by stress and drug misuse that includes structural and functional changes in limbic brain regions and the salience, default-mode, and frontoparietal networks. Effective strategies to prevent PTSD are needed to limit the negative consequences associated with the later development of a substance use disorder (SUD). In this review, we will examine the link between PTSD and SUDs, along with the resulting effects on memory, focusing on the connection between the development of an SUD in individuals who struggled with PTSD in adolescence. Neuroimaging has emerged as a powerful tool to provide insight into the brain mechanisms underlying the connection of PTSD in adolescence and the development of SUDs.

Changes in serotonin neurotransmission as assayed by microdialysis after acute, intermittent or chronic ethanol administration and withdrawal.

The serotonergic neurotransmitter system is involved in many ethanol-induced changes, including many behavioural alterations, as well as contributing to alcohol dependence and its withdrawal. This review has evaluated microdialysis studies where alterations in the serotonin system, that is, serotonin, 5-HT, or its metabolite 5-hydroxyindoleacetic acid, 5-HIAA, have been reported during different ethanol intoxication states, as well as in animals showing alcohol preference or not. Changes in 5-HT receptors and the 5-HT transporter are briefly reviewed to comprehend the significance of changes in microdialysate 5-HT concentrations. Changes in 5-HT content following acute, chronic and during ethanol withdrawal states are evaluated. In addition, the serotoninergic system was assessed in animals that have been genetically selected for alcohol preference to ascertain whether changes in this monoamine microdialysate content may contribute to alcohol preference. Changes occurred in 5-HT signalling in the limbic brain regions, increasing after acute ethanol administration in specific brain regions, particularly at higher doses, while chronic alcohol exposure essentially decreased serotonergic transmission. Such changes may play a pivotal role in emotion-driven craving and relapse. Depending on the dosage, mode of administration and consumption rate, ethanol affects specific brain regions in different ways, enhancing or reducing 5-HT microdialysate content, thereby inducing behavioural and cognitive functions and enhancing ethanol consumption. Microdialysis studies demonstrated that ethanol induces several alterations in 5-HT content as well as its metabolites, 5-HIAA and 5-HTOL, not only in its release from a specific brain region but also in the modifications of its different receptor subtypes and its transporter.

Neural correlates of the sound facilitation effect in the modified Simon task in older adults.

The ability to resolve interference declines with age and is attributed to neurodegeneration and reduced cognitive function and mental alertness in older adults. Our previous study revealed that task-irrelevant but environmentally meaningful sounds improve performance on the modified Simon task in older adults. However, little is known about neural correlates of this sound facilitation effect. Twenty right-handed older adults [mean age = 72 (SD = 4), 11 female] participated in the fMRI study. They performed the modified Simon task in which the arrows were presented either in the locations matching the arrow direction (congruent trials) or in the locations mismatching the arrow direction (incongruent trials). A total of 50% of all trials were accompanied by task-irrelevant but environmentally meaningful sounds. Participants were faster on the trials with concurrent sounds, independently of whether trials were congruent or incongruent. The sound effect was associated with activation in the distributed network of auditory, posterior parietal, frontal, and limbic brain regions. The magnitude of the behavioral facilitation effect due to sound was associated with the changes in activation of the bilateral auditory cortex, cuneal cortex, and occipital fusiform gyrus, precuneus, left superior parietal lobule (SPL) for No Sound vs. Sound trials. These changes were associated with the corresponding changes in reaction time (RT). Older adults with a recent history of falls showed greater activation in the left SPL than those without falls history. Our findings are consistent with the dedifferentiation hypothesis of cognitive aging. The facilitatory effect of sound could be achieved through recruitment of excessive neural resources, which allows older adults to increase attention and mental alertness during task performance. Considering that the SPL is critical for integration of multisensory information, individuals with slower task responses and those with a history of falls may need to recruit this region more actively than individuals with faster responses and those without a fall history to overcome increased difficulty with interference resolution. Future studies should examine the relationship among activation in the SPL, the effect of sound, and falls history in the individuals who are at heightened risk of falls.

A Comprehensive Review on Alzheimer’s Disease its Pathogenesis, Epidermiology, Diagnostics and Treatment

The global impact of Alzheimer's disease (AD) is significant. The current prevalence of Major Neurocognitive Disorder is estimated to affect approximately 44 million individuals. Presently, the United States harbors a population of approximately 6.2 million individuals who are afflicted by Alzheimer's disease (AD) dementia. It is of significance to highlight that mortality associated with Alzheimer's disease (AD) exceeds the combined mortality rates of both breast cancer and prostate cancer. Based on the findings of the National Institute on Aging, the frequency of Alzheimer's disease (AD) exhibits a twofold rise every five years subsequent to attaining the age of 65. Furthermore, with the ongoing process of population aging, an increasingly substantial portion of the population is affected by this particular condition. Based on forecasts, it is anticipated that the United States will experience a financial impact of $355 billion in 2021 as a result of Alzheimer's disease (AD).
 Furthermore, same projections indicate that this amount is expected to increase significantly to over $1.5 trillion by the year 2050. As a result, this would place a significant financial strain on the country. Alzheimer's disease (AD) is a neurodegenerative condition that is distinguished by the existence of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles consisting of hyperphosphorylated τ-protein. The aforementioned abnormal characteristics primarily present themselves inside the cortical and limbic regions of the human brain. The aforementioned ailment is characterized by the presence of memory impairment and a progressive deterioration of neurocognitive abilities. The atypical division of amyloid precursor protein (APP) by β-secretases and γ-secretases leads to the production of Aβ40 and Aβ42 individual molecules, which then undergo the process of oligomerization and aggregation, finally culminating in the formation of senile plaques. The aforementioned disease is additionally aggravated by pathogenic microorganisms, including the human immunodeficiency virus (HIV).
 Moreover, within the framework of disease pathophysiology, the presence of heightened amounts of Aβ peptides within the central nervous system induces the infiltration of microglial cells. Presently, there exists a notable focus within the realm of scientific inquiry on gaining a comprehensive understanding of the pathological nature of Alzheimer's disease (AD) by means of exploring diverse pathways.
 These mechanisms include the abnormal metabolism of tau proteins, the presence of β-amyloid, the inflammatory response, as well as the damage caused by cholinergic dysfunction and free radicals. The ultimate objective of this research is to develop efficacious treatments that can effectively halt or alter the progression of AD. The present study provides an analysis of the pathophysiological mechanisms underlying Alzheimer's disease, as well as an examination of the diagnostic methods employed in its identification. Furthermore, the review explores the many therapy modalities now utilized in managing this neurodegenerative disorder.

Integrative bioinformatics and artificial intelligence analyses of transcriptomics data identified genes associated with major depressive disorders including NRG1

Major depressive disorder (MDD) is a common mental disorder and is amongst the most prevalent psychiatric disorders. MDD remains challenging to diagnose and predict its onset due to its heterogeneous phenotype and complex etiology. Hence, early detection using diagnostic biomarkers is critical for rapid intervention. In this study, a mixture of AI and bioinformatics were used to mine transcriptomic data from publicly available datasets including 170 MDD patients and 121 healthy controls. Bioinformatics analysis using gene set enrichment analysis (GSEA) and machine learning (ML) algorithms were applied. The GSEA revealed that differentially expressed genes in MDD patients are mainly enriched in pathways related to immune response, inflammatory response, neurodegeneration pathways and cerebellar atrophy pathways. Feature selection methods and ML provided predicted models based on MDD-altered genes with ≥75% of accuracy. The integrative analysis between the bioinformatics and ML approaches identified ten key MDD-related biomarkers including NRG1, CEACAM8, CLEC12B, DEFA4, HP, LCN2, OLFM4, SERPING1, TCN1 and THBS1. Among them, NRG1, active in synaptic plasticity and neurotransmission, was the most robust and reliable to distinguish between MDD patients and healthy controls amongst independent external datasets consisting of a mixture of populations. Further evaluation using saliva samples from an independent cohort of MDD and healthy individuals confirmed the upregulation of NRG1 in patients with MDD compared to healthy controls. Functional mapping to the human brain regions showed NRG1 to have high expression in the main subcortical limbic brain regions implicated in depression. In conclusion, integrative bioinformatics and ML approaches identified putative non-invasive diagnostic MDD-related biomarkers panel for the onset of depression.

Preterm birth associated alterations in brain structure, cognitive functioning and behavior in children from the ABCD dataset.

Preterm birth is a global health problem and associated with increased risk of long-term developmental impairments, but findings on the adverse outcomes of prematurity have been inconsistent. Data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development (ABCD) Study. We identified 1706 preterm children and 1865 matched individuals as Control group and compared brain structure (MRI data), cognitive function and mental health symptoms. Results showed that preterm children had higher psychopathological risk and lower cognitive function scores compared to controls. Structural MRI analysis indicated that preterm children had higher cortical thickness in the medial orbitofrontal cortex, parahippocampal gyrus, temporal and occipital gyrus; smaller volumes in the temporal and parietal gyrus, cerebellum, insula and thalamus; and smaller fiber tract volumes in the fornix and parahippocampal-cingulum bundle. Partial correlation analyses showed that gestational age and birth weight were associated with ADHD symptoms, picvocab, flanker, reading, fluid cognition composite, crystallized cognition composite and total cognition composite scores, and measures of brain structure in regions involved with emotional regulation, attention and cognition. These findings suggest a complex interplay between psychopathological risk and cognitive deficits in preterm children that is associated with changes in regional brain volumes, cortical thickness, and structural connectivity among cortical and limbic brain regions critical for cognition and emotional well-being.

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

The peripartum period is accompanied by peripheral immune alterations to promote a successful pregnancy.We and others have also demonstrated significant neuroimmune changes that emerge during late pregnancy and persist postpartum, most prominently decreased microglia numbers within limbic brain regions. Here we hypothesized that microglial downregulation is important for the onset and display of maternal behavior. To test this, we recapitulated the peripartum neuroimmune profile by depleting microglia in non-mother (i.e., nulliparous) female rats who are typically not maternal but can be induced to behave maternally towards foster pups after repeated exposure, a process called maternal sensitization. BLZ945, a selective colony-stimulating factor 1 receptor (CSF1R) inhibitor, was administered systemically to nulliparous rats, which led to ~75% decrease in microglia number. BLZ- and vehicle-treated females then underwent maternal sensitization and tissue wasstained 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.

Maternal anxiety-driven modulation of fetal limbic connectivity designs a backbone linking neonatal brain functional topology to socio-emotional development in early childhood.

A link between maternal anxiety during pregnancy and adverse socio-emotional outcomes in childhood has been consistently sustained on the very early neurodevelopmental alteration of structural pathways between fetal limbic and cortical brain regions. In this study, we provide follow-up evidence for a feed-forward model linking (i) maternal anxiety, (ii) fetal functional neurodevelopment, (iii) neonatal functional network organization with (iv) socio-emotional neurobehavioral development in early childhood. Namely, we investigate a sample of 16 mother-fetus dyads and show how a maternal state-trait anxiety profile with pregnancy-specific worries can significantly influence functional synchronization patterns between regions of the fetal limbic system (i.e., hippocampus and amygdala) and the neocortex, as assessed through resting-state functional magnetic resonance imaging. Generalization of the findings was supported by leave-one-out cross-validation. We further show how this maternal-fetal cross-talk propagates to functional network topology in the neonate, specifically targeting connector hubs, and further maps onto socio-emotional profiles, assessed through Bayley-III socio-emotional scale in early childhood (i.e., in the 12-24 months range). Based on this evidence, we put forward the hypothesis of a "Maternal-Fetal-Neonatal Anxiety Backbone", through which neurobiological changes driven by maternal anxiety could trigger a divergence in the establishment of a cognitive-emotional development blueprint, in terms of the nascent functional homeostasis between bottom-up limbic and top-down higher-order neuronal circuitry.

Serotonin and the Brain

Major depressive disorder (MDD) is a highly prevalent and debilitating illness in the modern world. In the 1960s, the theory that low serotonin (5-HT) was a primary cause of MDD emerged due to the efficacy of 5-HT restoring drugs in treating depression. The 5-HT deficiency hypothesis of depression has since been criticized through studies not being able to directly tie low serotonin to MDD. The discovery of the antidepressant efficacy of the glutamatergic priming ketamine led to a reevaluation of depression pathophysiology. Modern perspectives view depression as an issue of disrupted neurocircuitry resulting from stress induced atrophy of certain limbic and cortical brain regions, such as the hippocampus and PFC, and hypertrophy in the fear evaluating amygdala, the reward evaluating nucleus accumbens, and the orbitofrontal cortex. Depression may be treated by supplementing psychotherapy with potentiating neuroplasticity, helping individuals relearn negative emotional associations and restoring dysfunctional neurocircuitry . 5-HT may be viewed as a vulnerability factor in developing depression due to its involvement in stress, as well as a treatment target which indirectly primes neuroplasticity. Other neurotransmitter systems similarly represent depressive risk factors and antidepressant targets, namely the noradrenergic and dopaminergic systems. Serotonergic antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs) see high rates of prescription due to their minimal side effects. They demonstrate slower efficacy than ketamine, whose dissociative side effects and potential for abuse are unideal, demanding further research of its mechanism to find safer and more effective antidepressant targets.

Double-Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing α-Synuclein.

Venglustat is a brain-penetrant, small molecule inhibitor of glucosylceramide synthase used in clinical testing for treatment of Parkinson's disease (PD). Despite beneficial effects in certain cellular and rodent models, patients with PD with mutations in GBA, the gene for lysosomal glucocerebrosidase, experienced worsening of their motor function under venglustat treatment (NCT02906020, MOVES-PD, phase 2 trial). The objective of this study was to evaluate venglustat in mouse models of PD with overexpression of wild-type α-synuclein. Mice overexpressing α-synuclein (Thy1-aSyn line 61) or Gba-mutated mice with viral vector-induced overexpression of α-synuclein in the substantia nigra were administered venglustat as food admixture. Motor and cognitive performance, α-synuclein-related pathology, and microgliosis were compared with untreated controls. Venglustat worsened motor function in Thy1-aSyn transgenics on the challenging beam and the pole test. Although venglustat did not alter the cognitive deficit in the Y-maze test, it alleviated anxiety-related behavior in the novel object recognition test. Venglustat reduced soluble and membrane-bound α-synuclein in the striatum and phosphorylated α-synuclein in limbic brain regions. Although venglustat reversed the loss of parvalbumin immunoreactivity in the basolateral amygdala, it tended to increase microgliosis and phosphorylated α-synuclein in the substantia nigra. Furthermore, venglustat also partially worsened motor performance and tended to increase neurofilament light chain in the cerebrospinal fluid in the Gba-deficient model with nigral α-synuclein overexpression and neurodegeneration. Venglustat treatment in two mouse models of α-synuclein overexpression showed that glucosylceramide synthase inhibition had differential detrimental or beneficial effects on behavior and neuropathology possibly related to brain region-specific effects. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PDIA3 Expression Is Altered in the Limbic Brain Regions of Triple-Transgenic Mouse Model of Alzheimer's Disease.

In the present study, we used a mouse model of Alzheimer's disease (AD) (3×Tg-AD mice) to longitudinally analyse the expression level of PDIA3, a protein disulfide isomerase and endoplasmic reticulum (ER) chaperone, in selected brain limbic areas strongly affected by AD-pathology (amygdala, entorhinal cortex, dorsal and ventral hippocampus). Our results suggest that, while in Non-Tg mice PDIA3 levels gradually reduce with aging in all brain regions analyzed, 3×Tg-AD mice showed an age-dependent increase in PDIA3 levels in the amygdala, entorhinal cortex, and ventral hippocampus. A significant reduction of PDIA3 was observed in 3×Tg-AD mice already at 6 months of age, as compared to age-matched Non-Tg mice. A comparative immunohistochemistry analysis performed on 3×Tg-AD mice at 6 (mild AD-like pathology) and 18 (severe AD-like pathology) months of age showed a direct correlation between the cellular level of Aβ and PDIA3 proteins in all the brain regions analysed, even if with different magnitudes. Additionally, an immunohistochemistry analysis showed the presence of PDIA3 in all post-mitotic neurons and astrocytes. Overall, altered PDIA3 levels appear to be age- and/or pathology-dependent, corroborating the ER chaperone's involvement in AD pathology, and supporting the PDIA3 protein as a potential novel therapeutic target for the treatment of AD.

Superstorm Sandy exposure in utero is associated with neurobehavioral phenotypes and brain structure alterations in childhood: A machine learning approach.

Prenatal maternal stress (PNMS), including exposure to natural disasters, has been shown to serve as a risk factor for future child psychopathology and suboptimal brain development, particularly among brain regions shown to be sensitive to stress and trauma exposure. However, statistical approaches deployed in most studies are usually constrained by a limited number of variables for the sake of statistical power. Explainable machine learning, on the other hand, enables the study of high data dimension and offers novel insights into the prominent subset of behavioral phenotypes and brain regions most susceptible to PNMS. In the present study, we aimed to identify the most important child neurobehavioral and brain features associated with in utero exposure to Superstorm Sandy (SS). By leveraging an explainable machine learning technique, the Shapley additive explanations method, we tested the marginal feature effect on SS exposures and examined the individual variable effects on disaster exposure. Results show that certain brain regions are especially sensitive to in utero exposure to SS. Specifically, in utero SS exposure was associated with larger gray matter volume (GMV) in the right caudate, right hippocampus, and left amygdala and smaller GMV in the right parahippocampal gyrus. Additionally, higher aggression scores at age 5 distinctly correlated with SS exposure. These findings suggest in utero SS exposure may be associated with greater aggression and suboptimal developmental alterations among various limbic and basal ganglia brain regions.