Region-specific Manner Research Articles

Optimized integration of metabolomics and lipidomics reveals brain region-specific changes of oxidative stress and neuroinflammation in type 1 diabetic mice with cognitive decline

IntroductionType 1 diabetes (T1D) causes cognitive decline and has been associated with brain metabolic disorders, but its potential molecular mechanisms remain unclear. ObjectivesThe purpose of this study was to explore the molecular mechanisms underlying T1D-induced cognitive impairment using metabolomics and lipidomics. MethodsWe developed an optimized integration approach of metabolomics and lipidomics for brain tissue based on UPLC-Q-TOF-MS and analyzed a comprehensive characterization of metabolite and lipid profiles in the hippocampus and frontal cortex of T1D male mice with cognitive decline (T1DCD) and age-matched control (CONT) mice. ResultsThe results show that T1DCD mice had brain metabolic disorders in a region-specific manner relative to CONT mice, and the frontal cortex exhibited a higher lipid peroxidation than the hippocampus in T1DCD mice. Based on metabolic changes, we found that microglia was activated under diabetic condition and thereby promoted oxidative stress and neuroinflammation, leading to neuronal injury, and this event was more pronounced in the frontal cortex than the hippocampus. ConclusionOur results suggest that brain region-specific shifts in oxidative stress and neuroinflammation may contribute to diabetic cognitive decline, and the frontal cortex could be the more vulnerable brain region than the hippocampus.

Changes in gut viral and bacterial species correlate with altered 1,2-diacylglyceride levels and structure in the prefrontal cortex in a depression-like non-human primate model

Major depressive disorder (MDD) is a debilitating mental disease, but its underlying molecular mechanisms remain obscure. Our previously established model of naturally occurring depression-like (DL) behaviors in Macaca fascicularis, which is characterized by microbiota-gut–brain (MGB) axis disturbances, can be used to interrogate how a disturbed gut ecosystem may impact the molecular pathology of MDD. Here, gut metagenomics were used to characterize how gut virus and bacterial species, and associated metabolites, change in depression-like monkey model. We identified a panel of 33 gut virus and 14 bacterial species that could discriminate the depression-like from control macaques. In addition, using lipidomic analyses of central and peripheral samples obtained from these animals, we found that the DL macaque were characterized by alterations in the relative abundance, carbon-chain length, and unsaturation degree of 1,2-diacylglyceride (DG) in the prefrontal cortex (PFC), in a brain region-specific manner. In addition, lipid-reaction analysis identified more active and inactive lipid pathways in PFC than in amygdala or hippocampus, with DG being a key nodal player in these lipid pathways. Significantly, co-occurrence network analysis showed that the DG levels may be relevant to the onset of negative emotions behaviors in PFC. Together our findings suggest that altered DG levels and structure in the PFC are hallmarks of the DL macaque, thus providing a new framework for understanding the gut microbiome’s role in depression.

Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by \u03b1-synuclein conformations

The protein α-synuclein, a key player in Parkinson’s disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible “prion-like” propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological α-synuclein, while pharmacological stabilization of multimers leads to a “prion-like” aggregation resistance. Together, our findings suggest that these disease-specific patterns of α-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and “prion-like” aggregation transmission enabled by the destabilization of local endogenous α-synuclein protein.

Post-weaning Social Isolation in Male and Female Prairie Voles: Impacts on Central and Peripheral Immune System.

The socially monogamous prairie vole (Microtus ochrogaster) offers a unique opportunity to examine the impacts of adolescent social isolation on the brain, immune system, and behavior. In the current study, male and female prairie voles were randomly assigned to be housed alone or with a same-sex cagemate after weaning (i.e., on postnatal day 21–22) for a 6-week period. Thereafter, subjects were tested for anxiety-like and depressive-like behaviors using the elevated plus maze (EPM) and Forced Swim Test (FST), respectively. Blood was collected to measure peripheral cytokine levels, and brain tissue was processed for microglial density in various brain regions, including the Nucleus Accumbens (NAcc), Medial Amygdala (MeA), Central Amygdala (CeA), Bed Nucleus of the Stria Terminalis (BNST), and Paraventricular Nucleus of the Hypothalamus (PVN). Sex differences were found in EPM and FST behaviors, where male voles had significantly lower total arm entries in the EPM as well as lower latency to immobility in the FST compared to females. A sex by treatment effect was found in peripheral IL-1β levels, where isolated males had a lower level of IL-1β compared to cohoused females. Post-weaning social isolation also altered microglial density in a brain region-specific manner. Isolated voles had higher microglial density in the NAcc, MeA, and CeA, but lower microglial density in the dorsal BNST. Cohoused male voles also had higher microglial density in the PVN compared to cohoused females. Taken together, these data suggest that post-weaning social housing environments can alter peripheral and central immune systems in prairie voles, highlighting a potential role for the immune system in shaping isolation-induced alterations to the brain and behavior.

Sleep-Dependent Facilitation of Visual Perceptual Learning Is Consistent with a Learning-Dependent Model

How sleep leads to offline performance gains in learning remains controversial. A use-dependent model assumes that sleep processing leading to performance gains occurs based on general cortical usage during wakefulness, whereas a learning-dependent model assumes that this processing is specific to learning. Here, we found evidence that supports a learning-dependent model in visual perceptual learning (VPL) in humans (both sexes). First, we measured the strength of spontaneous oscillations during sleep after two training conditions that required the same amount of training or visual cortical usage; one generated VPL (learning condition), while the other did not (interference condition). During a post-training nap, slow-wave activity (SWA) and sigma activity during non-rapid eye movement (NREM) sleep and theta activity during REM sleep were source localized to the early visual areas using retinotopic mapping. Inconsistent with a use-dependent model, only in the learning condition, sigma and theta activity, not SWA, increased in a trained region-specific manner and correlated with performance gains. Second, we investigated the roles of occipital sigma and theta activity during sleep. Occipital sigma activity during NREM sleep was significantly correlated with performance gains in presleep learning; however, occipital theta activity during REM sleep was correlated with presleep learning stabilization, shown as resilience to interference from postsleep learning in a trained region-specific manner. Occipital SWA was not associated with offline performance gains or stabilization. These results demonstrate that sleep processing leading to performance gains is learning dependent in VPL and involves occipital sigma and theta activity during sleep.SIGNIFICANCE STATEMENTThe present study shows strong evidence that could help resolve the long-standing controversy surrounding sleep processing that strengthens learning (performance gains). There are two conflicting models. A use-dependent model assumes that sleep processing leading to performance gains occurs because of general cortical usage during wakefulness, whereas a learning-dependent model assumes that processing occurs specifically for learning. Using visual perceptual learning and interference paradigms, we found that processing did not take place after general cortical usage. Moreover, sigma activity during non-rapid eye movement (REM) sleep and theta activity during REM sleep in occipital areas were found to be involved in processing, which is consistent with the learning-dependent model and not the use-dependent model. These results support the learning-dependent model.

Developmental Iron Deficiency Dysregulates TET Activity and DNA Hydroxymethylation in the Rat Hippocampus and Cerebellum

Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification of 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague Dawley rats were fed iron-deficient diet (ID; 4 mg/kg Fe) from gestational day 2 to generate iron-deficient anemic (IDA) offspring. Control dams were fed iron-sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, the hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p = 0.0105), with a corresponding increase in TET activity (p < 0.0001) and Tet3 expression (p < 0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p = 0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.

Cerebral Blood Perfusion is Improved Regionally After Shunt Surgery in the High-Pressure Hydrocephalic Brain.

To show the abnormal cerebral hemodynamics, in high-pressure hydrocephalic patients, could be restored by shunt surgery, and the tympanic membrane temperature (TMT) could be used to non-invasively monitor this recovery process. One-hundred-and-four patients, with high-pressure hydrocephalus (spinal tap opening pressure > 180 mmH2O), were prospectively enrolled in our study. The computed tomography perfusion (CTP) was scheduled for 7-10 days preand post-shunt surgery. The TMT and Glasgow Coma Scale (GCS) scores were collected during the same session. The CTP after the shunt surgery revealed a significant increase in cerebral blood volume (CBV) in both hemispheres (p < 0.05). More specifically, this CBV increase was observed in the midbrain, cerebellum, basal ganglion, temporal lobe, and frontal lobe regions (all p < 0.05). Simultaneously, patients' post-surgical TMT and GCS scores also increased compared to their pre-surgical scores since the first post-shunt follow-up (p < 0.01). Notably, while the GCS scores continued to increase during the post-shunt follow-up, the TMT exhibited a fluctuation period after the shunt and required seven days to reach a steady state. Our study revealed that a shunt could significantly increase cerebral perfusion in high-pressure hydrocephalic patients in a region-specific manner. During the perioperative period of hydrocephalus, TMT can be used to monitor cerebral hemodynamic changes.

Citizen-centered health platform concept for EU cross-border regions

The citizen-centered health platform project is intended to provide a platform that can be used in EU cross-border regions, where social and economic exchange occurs across national borders. The overriding challenges are: (a) social: improving citizen-centered health and care provision; (b) technical: providing a digital platform for networking citizens, service providers, and municipal actors; (c) economic: developing long-term successful (sustainable) business models/value chains. The platform should strengthen and expand existing networks and establish new regional networks. Each network addresses particular challenges and apply them in a region-specific manner. Here, the national boundary conditions and the interregional needs play an essential role. These objectives require sufficient participation of civil society representatives. Furthermore, the platform will establish an overarching, sustainable, and knowledge-based network of health experts. The platform is to be jointly developed and implemented in the regions and follow an open-access approach. Therefore, synergies will be shared more quickly, strengthening competencies and competitiveness. In addition to practice partners, scientific and municipal institutions and SMEs are involved. The actors thus contribute to scientific performance, innovative strength, and resilience.

Regional gray matter oligodendrocyte- and myelin-related measures are associated with differential susceptibility to stress-induced behavior in rats and humans

Individual reactions to traumatic stress vary dramatically, yet the biological basis of this variation remains poorly understood. Recent studies demonstrate the surprising plasticity of oligodendrocytes and myelin with stress and experience, providing a potential mechanism by which trauma induces aberrant structural and functional changes in the adult brain. In this study, we utilized a translational approach to test the hypothesis that gray matter oligodendrocytes contribute to traumatic-stress-induced behavioral variation in both rats and humans. We exposed adult, male rats to a single, severe stressor and used a multimodal approach to characterize avoidance, startle, and fear-learning behavior, as well as oligodendrocyte and myelin basic protein (MBP) content in multiple brain areas. We found that oligodendrocyte cell density and MBP were correlated with behavioral outcomes in a region-specific manner. Specifically, stress-induced avoidance positively correlated with hippocampal dentate gyrus oligodendrocytes and MBP. Viral overexpression of the oligodendrogenic factor Olig1 in the dentate gyrus was sufficient to induce an anxiety-like behavioral phenotype. In contrast, contextual fear learning positively correlated with MBP in the amygdala and spatial-processing regions of the hippocampus. In a group of trauma-exposed US veterans, T1-/T2-weighted magnetic resonance imaging estimates of hippocampal and amygdala myelin associated with symptom profiles in a region-specific manner that mirrored the findings in rats. These results demonstrate a species-independent relationship between region-specific, gray matter oligodendrocytes and differential behavioral phenotypes following traumatic stress exposure. This study suggests a novel mechanism for brain plasticity that underlies individual variance in sensitivity to traumatic stress.

Notch signaling mediates olfactory multiciliated cell specification.

Epithelial multiciliated cells (MCCs) use motile cilia to direct external fluid flow, the disruption of which is associated with human diseases in a broad array of organs such as those in the respiratory, reproductive, and renal systems. While many of the signaling pathways that regulate MCC formation in these organ systems have been identified, similar characterization of MCC differentiation in the developing olfactory system has been lacking. Here, using live cell tracking, targeted cell ablation, and temporally-specific inhibition of the Notch signaling pathway, we identify the earliest time window of zebrafish olfactory MCC (OMCC) differentiation and demonstrate these cells' derivation from peridermal cells. We also describe regionally segregated Notch signaling across time points of rapid OMCC differentiation and show that Notch signaling downregulation yields an increase in OMCCs, suggesting that OMCC fate is normally repressed in a region-specific manner during olfactory development. Finally, we describe Notch signaling's regulation of the differentiation/ciliogenesis-associated genes foxj1a and foxj1b. Taken together, these findings provide new insights into the origins and developmental programming of OMCCs in vivo.

Dietary tryptophan, tyrosine, and phenylalanine depletion induce reduced food intake and behavioral alterations in mice

Important precursors of monoaminergic neurotransmitters, dietary tryptophan (TRP), tyrosine, and phenylalanine (all referred to as TTP), play crucial roles in a wide range of behavioral and emotional functions. In the current study, we investigated whether diets devoid of TTP or diets deficient in TRP alone can affect body weight, behavioral characteristics, and gut microbiota, by comparing mice fed on these amino acids-depleted diets to mice fed on diets containing regular levels of amino acids. Both dietary TTP- and TRP-deprived animals showed a reduction in food intake and body weight. In behavioral analyses, the mice fed TTP-deprived diets were more active than mice fed diets containing regular levels of amino acids. The TRP-deprived group exhibited a reduction in serum TRP levels, concomitant with a decrease in serotonin and 5-hydroxyindoleacetic acid levels in some regions of the brain. The TTP-deprived group showed a reduction in TTP levels in the serum, concomitant with decreases in both phenylalanine and tyrosine levels in the hippocampus, as well as serotonin, norepinephrine, and dopamine concentrations in some regions of the brain. Regarding the effects of TRP or TTP deprivation on gut microbial ecology, the relative abundance of genus Roseburia was significantly reduced in the TTP-deprived group than in the dietary restriction control group. Interestingly, TTP was found even in the feces of mice fed TTP- and TRP-deficient diets, suggesting that TTP is produced by microbial or enzymatic digestion of the host-derived proteins. However, microbe generated TTP did not compensate for the systemic TTP deficiency induced by the lack of dietary TTP intake. Collectively, these results indicate that chronic dietary TTP deprivation induces decreased monoamines and their metabolites in a brain region-specific manner. The altered activities of the monoaminergic systems may contribute to increased locomotor activity.

Region-Specific KCC2 Rescue by rhIGF-1 and Oxytocin in a Mouse Model of Rett Syndrome.

Rett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified 3 key frontal brain regions showing KCC2 alterations in young adult mice, but not in postnatal P10 animals. We hypothesized that deficits in an IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor and OXT receptor levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.

The Effect of Valproic Acid Exposure throughout Development on Microglia Number in the Prefrontal Cortex, Hippocampus and Cerebellum

Microglia serve as resident immune cells in the brain, responding to insults and pathological developments. They have also been implicated in shaping synaptic development and regulation. The present study examined microglial cell density in a number of brain regions across select postnatal (P) ages along with the effects of valproic acid (VPA) on microglia density. Specifically, C57BL/6JCx3CR1+/GFP mice were examined for microglial cell number changes on P7, P14, P30, and P60 under baseline conditions and following 400 mg/kg VPA or saline. The prefrontal cortex (PFC), hippocampus and cerebellum were observed. Under control conditions, the results showed a shift in the number of microglia in these brain areas throughout development with a peak density in the hippocampus at P14 and an increase in PFC microglial numbers from P15 to P30. Interestingly, VPA treatment enhanced microglial numbers in a region-specific manner. VPA at P7 increased microglial cell number in the hippocampus and cerebellum whereas P14 VPA treatment altered microglial density in the cerebellum only. Cerebellar increases also occurred after VPA at P30, and were attended by an effect of increased numbers in the PFC. Finally, animals treated with VPA at P60 exhibited decreased microglia density in the hippocampus only. These results suggest rapid VPA-induced increases in microglial cell density in a developmentally-regulated fashion which differs across distinct brain areas. Furthermore, in the context of prior reports that early VPA causes excitotoxic damage, the present findings suggest early VPA exposure may provide a model for studying altered microglial responses to early toxicant challenge.

Sex and region-specific effects of variable stress on microglia morphology

Major Depressive Disorder (MDD) is a common and debilitating mood disorder that is more prevalent in women than men. In humans, PET imaging of microglia activation is currently being explored as a potential biomarker of MDD and suicidal ideation. Stress is a trigger for many mood disorders, including MDD. Microglial changes in morphology and activation state in response to stress has been reported in various brain regions, but most studies only examined male subjects. Here we report changes in microglia morphology in the nucleus accumbens (NAc) and subregions of the hippocampus (HPC) in both male and female mice following variable stress of 6 or 28 days in duration. Our data demonstrate that after 6 days of stress, microglia in the female NAc and dentate gyrus have a reduction in homeostatic associated morphology and an increase in primed microglia. After 28 days some of these sex specific stress effects were still present in microglia within the NAc but not the dentate gyrus. There were no effects of stress in either sex at either timepoint in CA1. In female mice, anti-inflammatory activation of microglia using rosiglitazone promoted sociability behavior after 6 days of stress. Furthermore, both drug and stress have impact on microglia morphology and activation state in the NAc. These data suggest that microglia morphology and activation state are altered by 6 days of variable stress in a region-specific manner and may contribute to, or potentially compensate for, the onset of stress susceptibility rather than impacting long term exposure to stress.

Localization and expression of the Mas-related G-protein coupled receptor member D (MrgD) in the mouse brain

Numerous studies in the last decades have provided evidence for the existence of a local renin-angiotensin system (RAS) in the central nervous system (CNS). Widespread distribution of the different RAS components in the brain demonstrates the pleiotropic role of this system in the structure and function of CNS. With the advent of new molecular techniques, a novel receptor has been identified within the beneficial arm of the RAS, the Mas-related G-protein coupled receptor D (MrgD), which can be stimulated by two heptapeptides, Ala1-(Ang-(1-7), also named alamandine, and Ang-(1-7). However, the biological and physiological relevance of this interaction remains obscure. Since several recent studies hinted at a role of MrgD in the CNS, we determined the distribution pattern of MrgD receptors in the adult mouse brain by using a genetic mouse model with tracers of MrgD expression. MrgD-positive cells could be identified in some forebrain areas, including cortex, hippocampus, amygdala, hypothalamus, habenular nuclei, striatum and pallidum, as well as in some mid-brain nuclei in a region-specific manner. The specific localization of MrgD in the reward- and limbic-related areas can hint at a role of MrgD in processes such as pain perception/modulation, synaptic plasticity, learning, memory and cognition.

Short-Term Sleep Fragmentation Dysregulates Autophagy in a Brain Region-Specific Manner.

In this study, we investigated autophagy, glial activation status, and corticotropin releasing factor (CRF) signaling in the brains of mice after 5 days of sleep fragmentation (SF). Three different brain regions including the striatum, hippocampus, and frontal cortex were selected for examination based on roles in sleep regulation and sensitivity to sleep disruption. For autophagy, we monitored the levels of various autophagic induction markers including beclin1, LC3II, and p62 as well as the levels of lysosomal associated membrane protein 1 and 2 (LAMP1/2) and the transcription factor EB (TFEB) which are critical for lysosome function and autophagy maturation stage. For the status of microglia and astrocytes, we determined the levels of Iba1 and GFAP in these brain regions. We also measured the levels of CRF and its cognate receptors 1 and 2 (CRFR1/2). Our results showed that 5 days of SF dysregulated autophagy in the striatum and hippocampus but not in the frontal cortex. Additionally, 5 days of SF activated microglia in the striatum but not in the hippocampus or frontal cortex. In the striatum, CRFR2 but not CRFR1 was significantly increased in SF-experienced mice. CRF did not alter its mRNA levels in any of the three brain regions assessed. Our findings revealed that autophagy processes are sensitive to short-term SF in a region-specific manner and suggest that autophagy dysregulation may be a primary initiator for brain changes and functional impairments in the context of sleep disturbances and disorders.

Na+/K+-ATPase activity is regionally regulated by acute hypoxia in naked mole-rat brain

Matching ATP supply and demand is key to neuronal hypoxia-tolerance and failure to achieve this balance leads to excitotoxic cell death in most adult mammalian brains. Ion pumping is the most energy-demanding process in the brain and some hypoxia-tolerant vertebrates coordinately down-regulate ion movement across neuronal membranes to reduce the workload of energy-expensive ion pumps, and particularly the Na+/K+-ATPase. Naked mole-rats are among the most hypoxia-tolerant mammals and achieve a hypometabolic state while maintaining brain [ATP] during severe hypoxia; however, whether ionic homeostasis is plastic in naked mole-rat brain is unknown. To examine this question, we exposed animals to 4 h of normoxia or moderate or severe hypoxia (11 or 3% O2, respectively) and measured changes in brain Na+/K+-ATPase activity. We found that 1) whole body metabolic rate decreased ∼25 and 75% in moderate and severe hypoxia, respectively, and 2) Na+/K+-ATPase activity decreased ∼50% in forebrain but increased 2-fold in cerebellum and was unchanged in brainstem. These results indicate that naked mole-rats acutely modulate brain energy demand in a region-specific manner to prioritize energy usage by the cerebellum. This may support exploration, navigation, and escape behaviours, while also enabling ATP savings when encountering hypoxia in nature.

Unilateral vocal nerve resection alters neurogenesis in the avian song system in a region-specific manner.

New neurons born in the adult brain undergo a critical period soon after migration to their site of incorporation. During this time, the behavior of the animal may influence the survival or culling of these cells. In the songbird song system, earlier work suggested that adult-born neurons may be retained in the song motor pathway nucleus HVC with respect to motor progression toward a target song during juvenile song learning, seasonal song restructuring, and experimentally manipulated song variability. However, it is not known whether the quality of song per se, without progressive improvement, may also influence new neuron survival. To test this idea, we experimentally altered song acoustic structure by unilateral denervation of the syrinx, causing a poor quality song. We found no effect of aberrant song on numbers of new neurons in HVC, suggesting that song quality does not influence new neuron culling in this region. However, aberrant song resulted in the loss of left-side dominance in new neurons in the auditory region caudomedial nidopallium (NCM), and a bilateral decrease in new neurons in the basal ganglia nucleus Area X. Thus new neuron culling may be influenced by behavioral feedback in accordance with the function of new neurons within that region. We propose that studying the effects of singing behaviors on new neurons across multiple brain regions that differentially subserve singing may give rise to general rules underlying the regulation of new neuron survival across taxa and brain regions more broadly.

Doxycycline promotes proteasome fitness in the central nervous system

Several studies reported that mitochondrial stress induces cytosolic proteostasis in yeast and C. elegans. Notably, inhibition of mitochondrial translation with doxcycyline decreases the toxicity of β-amyloid aggregates, in a C. elegans. However, how mitochondrial stress activates cytosolic proteostasis remains unclear. Further whether doxycycline has this effect in mammals and in disease relevant tissues also remains unclear. We show here that doxycycline treatment in mice drastically reduces the accumulation of proteins destined for degradation by the proteasome in a CNS region-specific manner. This effect is associated with the activation of the ERα axis of the mitochondrial unfolded protein response (UPRmt), in both males and females. However, sexually dimorphic mechanisms of proteasome activation were observed. Doxycycline also activates the proteasome in fission yeast, where ERα is not expressed. Rather, the ancient ERα-coactivator Mms19 regulates this response in yeast. Our results suggest that the UPRmt initiates a conserved mitochondria-to-cytosol stress signal, resulting in proteasome activation, and that this signal has adapted during evolution, in a sex and tissue specific-manner. Therefore, while our results support the use of doxycycline in the prevention of proteopathic diseases, they also indicate that sex is an important variable to consider in the design of future clinical trials using doxycycline.

Hypothalamic Perineuronal Nets Are Regulated by Sex and Dietary Interventions.

Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus play an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.