Restoring Serotonergic Homeostasis in the Lateral Hypothalamus Rescues Sleep Disturbances Induced by Early-Life Obesity.

Early-life obesity predisposes to obesity in adulthood, a condition with broad medical implications including sleep disorders, which can exacerbate metabolic disturbances and disrupt cognitive and affective behaviors. In this study, we examined the long-term impact of transient peripubertal diet-induced obesity (ppDIO, induced between 4 and 10 weeks of age) on sleep-wake behavior in male mice. EEG and EMG recordings revealed that ppDIO increases sleep during the active phase but reduces resting-phase sleep quality. This impaired sleep phenotype persisted for up to 1 year, although animals were returned to a non-obesiogenic diet from postnatal week 11 onwards. To better understand the mechanisms responsible for the ppDIO-induced alterations in sleep, we focused on the lateral hypothalamus (LH). Mice exposed to ppDIO did not show altered mRNA expression levels of orexin and melanin-concentrating hormone, two peptides that are important for sleep-wake behavior and food intake. Conversely, the LH of ppDIO-exposed mice had reduced contents of serotonin (5-hydroxytryptamine, 5-HT), a neurotransmitter involved in both sleep-wake and satiety regulation. Interestingly, an acute peripheral injection of the satiety-signaling peptide YY 3-36 increased 5-HT turnover in the LH and ameliorated the ppDIO-induced sleep disturbances, suggesting the therapeutic potential of this peptide. These findings provide new insights into how sleep-wake behavior is programmed during early life and how peripheral and central signals are integrated to coordinate sleep.SIGNIFICANCE STATEMENT Adult physiology and behavior are strongly influenced by dynamic reorganization of the brain during puberty. The present work shows that obesity during puberty leads to persistently dysregulated patterns of sleep and wakefulness by blunting serotonergic signaling in the lateral hypothalamus. It also shows that pharmacological mimicry of satiety with peptide YY3-36 can reverse this neurochemical imbalance and acutely restore sleep composition. These findings add insight into how innate behaviors such as feeding and sleep are integrated and suggest a novel mechanism through which diet-induced obesity during puberty imposes its long-lasting effects on sleep-wake behavior.

The Arctic/Swedish APP mutation alters the impact of chronic stress on cognition in mice.

Chronic stress is a major risk factor for developing Alzheimer's disease (AD) and promotes the processing of amyloid precursor protein (APP) to ß-amyloid (Aß). However, the precise relationship of stress and disease-typical cognitive decline is presently not well understood. The aim of this study was to investigate how early life stress may affect cognition in adult mice with and without soluble Aß pathology typical for the early stages of the disease. We focussed on sustained attention and response control, aspects of cognition mediated by the prefrontal cortex that are consistently impaired both in early AD and after chronic stress exposure. Young wild-type mice as well as transgenic arcAß mice overexpressing the hAPParc/swe transgene were exposed to a chronic unpredictable stress paradigm (age 3-8 weeks). At 15 weeks, these mice were tested on the 5-choice serial reaction time task, a test of sustained attention and executive control. We found that, expectedly, chronic stress increased impulsive choices and impaired sustained attention in wild-type mice. However, the same treatment reduced impulsivity and did not interfere with sustained attention in arcAß mice. These findings suggest an unexpected interaction between chronic stress and Aß whereby Aß-pathology caused by the hAPParc/swe mutation prevented and/or reversed stress-induced cognitive changes through mechanisms that deserve further investigation. They also indicate that Aß, in modest amounts, may have a beneficial role for cognitive stability, for example by protecting neural networks from the impact of further physiological or behavioural stress.

Stress and the Etiopathogenesis of Alzheimer's Disease and Depression.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex physiopathology whose initiators are poorly defined. Accumulating clinical and experimental evidence suggests a causal role of lifetime stress in AD. This chapter summarizes current knowledge about how chronic stress and its accompanying high levels of glucocorticoid (GC) secretion, trigger the two main pathomechanisms of AD: (i) misprocessing of amyloid precursor protein (APP) and the generation of amyloid beta (Aß) and (ii) Tau hyperphosphorylation and aggregation. Given that depression is a well-known stress-related illness, and the evidence that depression may precede AD, this chapter also explores neurobiological mechanisms that may be common to depressive and AD pathologies. This review also discusses emerging insights into the role of Tau and its malfunction in disrupting neuronal cascades and neuroplasticity and, thus triggering brain pathology.

Tau protein is essential for stress-induced brain pathology.

Exposure to chronic stress is frequently accompanied by cognitive and affective disorders in association with neurostructural adaptations. Chronic stress was previously shown to trigger Alzheimer's-like neuropathology, which is characterized by Tau hyperphosphorylation and missorting into dendritic spines followed by memory deficits. Here, we demonstrate that stress-driven hippocampal deficits in wild-type mice are accompanied by synaptic missorting of Tau and enhanced Fyn/GluN2B-driven synaptic signaling. In contrast, mice lacking Tau [Tau knockout (Tau-KO) mice] do not exhibit stress-induced pathological behaviors and atrophy of hippocampal dendrites or deficits of hippocampal connectivity. These findings implicate Tau as an essential mediator of the adverse effects of stress on brain structure and function.

Tau Deletion Prevents Stress-Induced Dendritic Atrophy in Prefrontal Cortex: Role of Synaptic Mitochondria.

Tau protein in dendrites and synapses has been recently implicated in synaptic degeneration and neuronal malfunction. Chronic stress, a well-known inducer of neuronal/synaptic atrophy, triggers hyperphosphorylation of Tau protein and cognitive deficits. However, the cause-effect relationship between these events remains to be established. To test the involvement of Tau in stress-induced impairments of cognition, we investigated the impact of stress on cognitive behavior, neuronal structure, and the synaptic proteome in the prefrontal cortex (PFC) of Tau knock-out (Tau-KO) and wild-type (WT) mice. Whereas exposure to chronic stress resulted in atrophy of apical dendrites and spine loss in PFC neurons as well as significant impairments in working memory in WT mice, such changes were absent in Tau-KO animals. Quantitative proteomic analysis of PFC synaptosomal fractions, combined with transmission electron microscopy analysis, suggested a prominent role for mitochondria in the regulation of the effects of stress. Specifically, chronically stressed animals exhibit Tau-dependent alterations in the levels of proteins involved in mitochondrial transport and oxidative phosphorylation as well as in the synaptic localization of mitochondria in PFC. These findings provide evidence for a causal role of Tau in mediating stress-elicited neuronal atrophy and cognitive impairment and indicate that Tau may exert its effects through synaptic mitochondria.

Selective inhibitors of the FK506-binding protein 51 by induced fit.

The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.

Glucose intolerance after chronic stress is related with downregulated PPAR-γ in adipose tissue.

BACKGROUND: Chronic stress is associated with increased risk of glucose intolerance and cardiovascular diseases, albeit through undefined mechanisms. With the aim of gaining insights into the latter, this study examined the metabolic profile of young adult male rats that were exposed to chronic unpredictable stress. METHODS: Young adult male rats were submitted to 4 weeks of chronic unpredictable stress and allowed to recover for 5 weeks. An extensive analysis including of morphologic, biochemical and molecular parameters was carried out both after chronic unpredictable stress and after recovery from stress. RESULTS: After 28 days of chronic unpredictable stress (CUS) the animals submitted to this protocol displayed less weight gain than control animals. After 5 weeks of recovery the weight gain rebounded to similar values of controls. In addition, following CUS, fasting insulin levels were increased and were accompanied by signs of impaired glucose tolerance and elevated serum corticosteroid levels. This biochemical profile persisted into the post-stress recovery period, despite the restoration of baseline corticosteroid levels. The mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-γ and lipocalin-2 in white adipose tissue were, respectively, down- and up-regulated. CONCLUSIONS: Reduction of PPAR-γ expression and generation of a pro-inflammatory environment by increased lipocalin-2 expression in white adipose tissue may contribute to stress-induced glucose intolerance.

Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration.

Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

Non-receptor-tyrosine kinases integrate fast glucocorticoid signaling in hippocampal neurons.

Despite numerous descriptions of rapid effects of corticosterone on neuronal function, the intracellular mechanisms responsible for these changes remain elusive. The present comprehensive analysis reveals that signaling from a membrane-located G protein-coupled receptor activates PKC, Akt/PKB, and PKA, which subsequently trigger the phosphorylation of the tyrosine kinases Pyk2, Src, and Abl. These changes induce rapid cytoskeletal rearrangements (increased PSD-95 co-clustering) within the post-synaptic density; these events are accompanied by increased surface NMDA receptor expression, reflecting corticosterone-induced inhibition of NMDA receptor endocytosis. Notably, none of these signaling mechanisms require de novo protein synthesis. The observed up-regulation of ERK1/2 (downstream of NMDA receptor signaling) together with the fact that c-Abl integrates cytoplasmic and nuclear functions introduces a potential mechanism through which rapid signaling initiated at the plasma membrane may eventually determine the long term integrated response to corticosterone by impacting on the transcriptional machinery that is regulated by classical, nuclear mineralocorticoid, and glucocorticoid receptors.

Neuropathology of stress.

Environmental challenges are part of daily life for any individual. In fact, stress appears to be increasingly present in our modern, and demanding, industrialized society. Virtually every aspect of our body and brain can be influenced by stress and although its effects are partly mediated by powerful corticosteroid hormones that target the nervous system, relatively little is known about when, and how, the effects of stress shift from being beneficial and protective to becoming deleterious. Decades of stress research have provided valuable insights into whether stress can directly induce dysfunction and/or pathological alterations, which elements of stress exposure are responsible, and which structural substrates are involved. Using a broad definition of pathology, we here review the "neuropathology of stress" and focus on structural consequences of stress exposure for different regions of the rodent, primate and human brain. We discuss cytoarchitectural, neuropathological and structural plasticity measures as well as more recent neuroimaging techniques that allow direct monitoring of the spatiotemporal effects of stress and the role of different CNS structures in the regulation of the hypothalamic-pituitary-adrenal axis in human brain. We focus on the hypothalamus, hippocampus, amygdala, nucleus accumbens, prefrontal and orbitofrontal cortex, key brain regions that not only modulate emotions and cognition but also the response to stress itself, and discuss disorders like depression, post-traumatic stress disorder, Cushing syndrome and dementia.

Early and specific detection of Alzheimer's disease: more than a (virtual) reality?

This scientific commentary refers to 'Path integration deficits are associated with phosphorylated tau accumulation in the entorhinal cortex', by Koike et al. (https://doi.org/10.1093/braincomms/fcad359).

Immunoglobulin G Fc receptor deficiency prevents Alzheimer-like pathology and cognitive impairment in mice.

Alzheimer's disease is a severely debilitating disease of high and growing proportions. Hypercholesterolaemia is a key risk factor in sporadic Alzheimer's disease that links metabolic disorders (diabetes, obesity and atherosclerosis) with this pathology. Hypercholesterolaemia is associated with increased levels of immunoglobulin G against oxidized lipoproteins. Patients with Alzheimer's disease produce autoantibodies against non-brain antigens and specific receptors for the constant Fc region of immunoglobulin G have been found in vulnerable neuronal subpopulations. Here, we focused on the potential role of Fc receptors as pathological players driving hypercholesterolaemia to Alzheimer's disease. In a well-established model of hypercholesterolaemia, the apolipoprotein E knockout mouse, we report increased brain levels of immunoglobulin G and upregulation of activating Fc receptors, predominantly of type IV, in neurons susceptible to amyloid ß accumulation. In these mice, gene deletion of γ-chain, the common subunit of activating Fc receptors, prevents learning and memory impairments without influencing cholesterolaemia and brain and serum immunoglobulin G levels. These cognition-protective effects were associated with a reduction in synapse loss, tau hyperphosphorylation and intracellular amyloid ß accumulation both in cortical and hippocampal pyramidal neurons. In vitro, activating Fc receptor engagement caused synapse loss, tau hyperphosphorylation and amyloid ß deposition in primary neurons by a mechanism involving mitogen-activated protein kinases and ß-site amyloid precursor protein cleaving enzyme 1. Our results represent the first demonstration that immunoglobulin G Fc receptors contribute to the development of hypercholesterolaemia-associated features of Alzheimer's disease and suggest a new potential target for slowing or preventing Alzheimer's disease in hypercholesterolaemic patients.

Stress acts cumulatively to precipitate Alzheimer's disease-like tau pathology and cognitive deficits.

Stressful life experiences are likely etiological factors in sporadic forms of Alzheimer's disease (AD). Many AD patients hypersecrete glucocorticoids (GCs), and their GC levels correlate with the rate of cognitive impairment and extent of neuronal atrophy. Severity of cognitive deficits in AD correlates strongly with levels of hyperphosphorylated forms of the cytoskeletal protein TAU, an essential mediator of the actions of amyloid ß (Aß), another molecule with a key pathogenic role in AD. Our objective was to investigate the sequential interrelationships between these various pathogenic elements, in particular with respect to the mechanisms through which stress might precipitate cognitive decline. We thus examined whether stress, through the mediation of GCs, influences TAU hyperphosphorylation, a critical and early event in the cascade of processes leading to AD pathology. Results from healthy, wild-type, middle-aged rats show that chronic stress and GC induce abnormal hyperphosphorylation of TAU in the hippocampus and prefrontal cortex (PFC), with contemporaneous impairments of hippocampus- and PFC-dependent behaviors. Exogenous GC potentiated the ability of centrally infused Aß to induce hyperphosphorylation of TAU epitopes associated with AD and cytoplasmic accumulation of TAU, while previous exposure to stress aggravated the biochemical and behavioral effects of GC in Aß-infused animals. Thus, lifetime stress/GC exposure may have a cumulative impact on the onset and progress of AD pathology, with TAU hyperphosphorylation serving to transduce the negative effects of stress and GC on cognition.

Stress shifts the response of the bed nucleus of the stria terminalis to an anxiogenic mode.

The bed nucleus of the stria terminalis (BNST) is critically implicated in anxiety behavior and control of the hypothalamus-pituitary-adrenal axis. Having previously shown that chronic stress triggers dendritic/synaptic remodeling in specific nuclei of the BNST, we characterised the pattern of activation of neurons within different regions of the BNST under basal conditions and after an anxiogenic stimulus in control and stressed rats. Under basal conditions, stressed, but not control, animals displayed increased cFOS expression in the dorsomedial nucleus and decreased activation of the principal nucleus. This pattern resembled that observed in controls that had been exposed to the anxiogenic stimulus. Subsequent analysis of various BNST subnuclei revealed differential patterns of gene expression in controls and stressed animals. We found decreased levels of corticotropin-releasing hormone 1 receptor mRNA expression in the dorsomedial and fusiform nuclei, and a global increase in the levels of corticotropin-releasing hormone 2 receptor in the principal nucleus. In addition, we found subnuclei-specific increases in GABA(A) and NR2B receptors in stressed animals, which suggest changes in the GABAergic and glutamergic innervation of the BNST. Importantly, these findings were associated with increased anxiety-like behavior and impaired control of the hypothalamus-pituitary-adrenal axis in stressed animals. In summary, these data reveal that chronic stress shifts the pattern of response of the BNST to an anxiogenic mode and provide new information on the underlying mechanisms of the stress-induced hypercorticalism and hyperanxious status.

Depletion of the neural precursor cell pool by glucocorticoids.

OBJECTIVE: Glucocorticoids (GCs) are indicated for a number of conditions in obstetrics and perinatal medicine; however, the neurodevelopmental and long-term neurological consequences of early-life GC exposure are still largely unknown. Preclinical studies have demonstrated that GCs have a major influence on hippocampal cell turnover by inhibiting neurogenesis and stimulating apoptosis of mature neurons. Here we examined the fate of the limited pool of neural progenitor cells (NPCs) after GC administration during neonatal development; the impact of this treatment on hippocampal structure was also studied. METHODS: Phenotype-specific genetic and antigenic markers were used to identify cultured NPCs at various developmental stages; the survival of these cells was monitored after exposure to the synthetic glucocorticoid dexamethasone (DEX). In addition, the effects of neonatal DEX treatment on the neurogenic potential of the rat hippocampus were examined by monitoring the incorporation of bromodeoxyuridine and expression of Ki67 antigen at various postnatal ages. RESULTS: Multipotent nestin-expressing NPCs and Talpha1-tubulin-expressing immature neurons succumb to GC-induced apoptosis in primary hippocampal cultures. Neonatal GC treatment results in marked apoptosis among the proliferating population of cells in the dentate gyrus, depletes the NPC pool, and leads to significant and sustained reductions in the volume of the dentate gyrus. INTERPRETATION: Both NPCs and immature neurons in the hippocampus are sensitive to the proapoptotic actions of GCs. Depletion of the limited NPC pool during early life retards hippocampal growth, thus allowing predictions about the potential neurological and psychiatric consequences of neonatal GC exposure.

Leveraging Neuroscience to Fight Stigma Around Mental Health.

Labels serve as identifiers and convenient descriptors of inanimate and animate objects. In humans, given labels can easily become part of an individual's self-perceived identity. Negative labels ascribed to a person can result in internalized stigma, a state that will shape the subject's biography. This can ultimately impact the person's mental and physical health since perceived and/or anticipated stigma discourages the use of social and health services. Per definition, stigma involves labeling of persons with physical, mental, or social characteristics that do not match the observer's arbitrarily conditioned and calibrated sense of norms (public stigma); such labeling may eventually become embedded in rules, regulations, and laws (structural stigma). Internalized stigma projects onto a person's emotions and actions. Public (enacted) stigma results from stereotyping (collectively agreed-upon notions about a group of persons that are used to categorize these people) and devaluation, which subsequently leads to social distancing, discrimination, and blatant abuse of human rights. Much of what we know about stigma results from research in the psychosocial sciences and, more recently, from social neuroscience. The stigma around mental health has generated much attention in the field of psychiatry where, to date, most research has focussed on epidemiology and anti-stigma interventions. This essay intends to stimulate thought, debate, and research within the behavioral neuroscience community and, therefore, to inform evidence-based design and implementation of neuroscience-based approaches by other professionals working towards the elimination of the stigma attached to mental illness. The article starts by considering the concept of stigma and the psychological processes that give rise to the phenomenon; it also considers how projected and perceived stigma are multiplied. Finally, after a brief review of the few existing neuroscientific explorations of stigma, gaps in our knowledge of the neurobiological basis of stigma are identified and discussed.

Brain Expression, Physiological Regulation and Role in Motivation and Associative Learning of Peroxisome Proliferator-activated Receptor γ.

Like other members of the superfamily of nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ), is a ligand-activated transcription factor known for its insulin-sensitizing actions in the periphery. Despite only sparse evidence for PPARγ in the CNS, many reports suggest direct PPARγ-mediated actions in the brain. This study aimed to (i) map PPARγ expression in rodent brain areas, involved in the regulation of cognitive, motivational, and emotional functions, (ii) examine the regulation of central PPARγ by physiological variables (age, sex, obesity); (iii) chemotypically identify PPARγ-expressing cells in the frontal cortex (FC) and hippocampus (HP); (iv) study whether activation of PPARγ by pioglitazone (Pio) in FC and HP cells can induce target gene expression; and (v) demonstrate the impact of activated PPARγ on learning behavior and motivation. Immunoreactive PPARγ was detectable in specific sub-nuclei/subfields of the FC, HP, nucleus accumbens, amygdala, hypothalamus, thalamus, and granular layers of the cerebellum. PPARγ protein levels were upregulated during aging and in high fat diet-induced obesity. PPARγ mRNA expression was upregulated in the amygdala of females (but not males) that were made obese. Neural precursor cells, mature neurons, and astrocytes in primary FC and HP cultures were shown to express PPARγ. Pioglitazone dose-dependently upregulated PPARγ target genes in manner that was specific to the origin (FC or HP) of the cultures. Lastly, administration of Pio impaired motivation and associative learning. Collectively, we provide evidence for the presence of regulatable PPARγ in the brain and demonstrate their participation the regulation of key behaviors.

Corrigendum: Activated PPARγ Abrogates Misprocessing of Amyloid Precursor Protein, Tau Missorting and Synaptotoxicity.

[This corrects the article DOI: 10.3389/fncel.2019.00239.].

Blunted leptin sensitivity during hedonic overeating can be reinstated by activating galanin 2 receptors (Gal2R) in the lateral hypothalamus.

AIM: Since foods with high hedonic value are often consumed in excess of energetic needs, this study was designed to identify the mechanisms that may counter anorexigenic signalling in the presence of hedonic foods in lean animals. METHODS: Mice, in different states of satiety (fed/fasted, or fed/fasted and treated with ghrelin or leptin, respectively), were allowed to choose between high-fat/high-sucrose and standard foods. Intake of each food type and the activity of hypothalamic neuropetidergic neurons that regulate appetite were monitored. In some cases, food choice was monitored in leptin-injected fasted mice that received microinjections of galanin receptor agonists into the lateral hypothalamus. RESULTS: Appetite-stimulating orexin neurons in the lateral hypothalamus are rapidly activated when lean, satiated mice consume a highly palatable food (PF); such activation (upregulated c-Fos expression) occurred even after administration of the anorexigenic hormone leptin and despite intact leptin signalling in the hypothalamus. The ability of leptin to restrain PF eating is restored when a galanin receptor 2 (Gal2R) agonist is injected into the lateral hypothalamus. CONCLUSION: Hedonically-loaded foods interrupt the inhibitory actions of leptin on orexin neurons and interfere with the homeostatic control of feeding. Overeating of palatable foods can be curtailed in lean animals by activating Gal2R in the lateral hypothalamus.

Glucocorticoids and neuro- and behavioural development.

Epidemiological evidence links exposure to stress hormones during fetal or early postnatal development with lifetime prevalence of cardiac, metabolic, auto-immune, neurological and psychiatric disorders. This has led to the concept of 'developmental programming through stress'. Importantly, these effects (specifically, hypertension, hyperglycaemia and neurodevelopmental and behavioural abnormalities) can be reproduced by exposure to high glucocorticoid levels, indicating a crucial role of glucocorticoids in their causation. However, there can be important differences in outcome, depending on the exact time of exposure, as well as duration and receptor selectivity of the glucocorticoid applied. The mechanisms underlying programming by stress are still unclear but it appears that these environmental perturbations exploit epigenetic modifications of DNA and/or histones to induce stable modifications of gene expression. Programming of neuro- and behavioural development by glucocorticoids and stress are important determinants of lifetime health and should be a consideration when choosing treatments in obstetric and neonatal medicine.