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BioRxiv : the Preprint Server For... Sep 2023Women are the main target of intimate partner violence (IPV), which is escalating worldwide. Mechanisms subtending IPV-related disorders, such as anxiety, depression and...
Women are the main target of intimate partner violence (IPV), which is escalating worldwide. Mechanisms subtending IPV-related disorders, such as anxiety, depression and PTSD, remain unclear. We employed a mouse model molded on an IPV scenario (male female prolonged violent interaction) to unearth the neuroendocrine alterations triggered by an aggressive male mouse on the female murine brain. Experimental IPV (EIPV) prompted marked anxiety-like behavior in young female mice, coincident with high circulating/cerebral corticosterone levels. The hippocampus of EIPV-inflicted female animals displayed neuronal loss, reduced BrdU-DCX-positive nuclei, decreased mature DCX-positive cells, and diminished dendritic arborization level in the dentate gyrus (DG), features denoting impaired neurogenesis and neuronal differentiation. These hallmarks were associated with marked down-regulation of estrogen receptor β (ERβ) density in the hippocampus, especially in the DG and dependent prosurvival ERK signaling. Conversely, ERα expression was unchanged. After EIPV, the DG harbored lowered local BDNF pools, diminished TrkB phosphorylation, and elevated glucocorticoid receptor phosphorylation. In unison, ERβ KO mice had heightened anxiety-like behavior and curtailed BDNF levels at baseline, despite enhanced circulating estradiol levels, while dying prematurely during EIPV. Thus, reiterated male-to-female violence jeopardizes hippocampal homeostasis in the female brain, perturbing ERβ/BDNF signaling, thus instigating anxiety and chronic stress.
PubMed: 37790349
DOI: 10.1101/2023.09.23.559092 -
Aging Jan 2024GV1001, which mimics the activity of human telomerase reverse transcriptase, protects neural cells from amyloid beta (Aβ) toxicity and other stressors through...
GV1001, which mimics the activity of human telomerase reverse transcriptase, protects neural cells from amyloid beta (Aβ) toxicity and other stressors through extra-telomeric function, as noted in our prior studies. As per a recent phase II clinical trial, it improves cognitive function in patients with moderate to severe dementia. However, the underlying protective mechanisms remain unclear. This study aimed to investigate the effects of GV1001 on neurodegeneration, senescence, and survival in triple transgenic Alzheimer's disease (3xTg-AD) mice. GV1001 (1 mg/kg) was subcutaneously injected into old 3xTg-AD mice thrice a week until the endpoint for sacrifice, and survival was analysed. Magnetic resonance imaging (MRI) and Prussian blue staining (PBS) were performed to evaluate entry of GV1001 entrance into the brain. Diverse molecular studies were performed to investigate the effect of GV1001 on neurodegeneration and cellular senescence in AD model mice, with a particular focus on BACE, amyloid beta (Aβ), phosphorylated tau, volume of dentate gyrus, β-galactosidase positive cells, telomere length, telomerase activity, and ageing-associated proteins. GV1001 crossed the blood-brain barrier, as confirmed by assessing the status of ferrocenecarboxylic acid-conjugated GV1001 using magnetic resonance imaging and PBS. GV1001 increased the survival of 3xTg-AD mice. It decreased BACE and Aβ levels, neurodegeneration (i.e., reduced CA1, CA3 and dentate gyrus volume, decreased levels of senescence-associated β-galactosidase positive cells, and increased telomere length and telomerase activity), and levels of ageing-associated proteins. We suggest that GV1001 exerts anti-ageing effects in 3xTg-AD mice by reducing neurodegeneration and senescence, which contributes to improved survival.
Topics: Mice; Humans; Animals; Amyloid beta-Peptides; Longevity; Mice, Transgenic; Telomerase; Alzheimer Disease; Aging; Disease Models, Animal; beta-Galactosidase; tau Proteins; Amyloid beta-Protein Precursor
PubMed: 38301041
DOI: 10.18632/aging.205489 -
CNS Neuroscience & Therapeutics Nov 2023Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F) is a serine/threonine phosphatase, and its dysfunction in depression in the hippocampal dentate gyrus has been...
AIMS
Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F) is a serine/threonine phosphatase, and its dysfunction in depression in the hippocampal dentate gyrus has been previously identified. Nevertheless, its role in depression of another critical emotion-controlling brain region, the medial prefrontal cortex (mPFC), remains unclear. We explored the functional relevance of PPM1F in the pathogenesis of depression.
METHODS
The gene expression levels and colocalization of PPM1F in the mPFC of depressed mice were measured by real-time PCR, western blot and immunohistochemistry. An adeno-associated virus strategy was applied to determine the impact of knockdown or overexpression of PPM1F in the excitatory neurons on depression-related behaviors under basal and stress conditions in both male and female mice. The neuronal excitability, expression of p300 and AMPK phosphorylation levels in the mPFC after knockdown of PPM1F were measured by electrophysiological recordings, real-time PCR and western blot. The depression-related behavior induced by PPM1F knockdown after AMPKα2 knockout or the antidepressant activity of PPM1F overexpression after inhibiting acetylation activity of p300 was evaluated.
RESULTS
Our results indicate that the expression levels of PPM1F were largely decreased in the mPFC of mice exposed to chronic unpredictable stress (CUS). Behavioral alterations relevant to depression emerged with short hairpin RNA (shRNA)-mediated genetic knockdown of PPM1F in the mPFC, while overexpression of PPM1F produced antidepressant activity and ameliorated behavioral responses to stress in CUS-exposed mice. Molecularly, PPM1F knockdown decreased the excitability of pyramidal neurons in the mPFC, and restoring this low excitability decreased the depression-related behaviors induced by PPM1F knockdown. PPM1F knockdown reduced the expression of CREB-binding protein (CBP)/E1A-associated protein (p300), a histone acetyltransferase (HAT), and induced hyperphosphorylation of AMPK, resulting in microglial activation and upregulation of proinflammatory cytokines. Conditional knockout of AMPK revealed an antidepressant phenotype, which can also block depression-related behaviors induced by PPM1F knockdown. Furthermore, inhibiting the acetylase activity of p300 abolished the beneficial effects of PPM1F elevation on CUS-induced depressive behaviors.
CONCLUSION
Our findings demonstrate that PPM1F in the mPFC modulates depression-related behavioral responses by regulating the function of p300 via the AMPK signaling pathway.
Topics: Animals; Female; Male; Mice; AMP-Activated Protein Kinases; Antidepressive Agents; Disease Models, Animal; Phosphoprotein Phosphatases; Prefrontal Cortex; RNA, Small Interfering; Signal Transduction; Stress, Psychological
PubMed: 37309288
DOI: 10.1111/cns.14293 -
Neurobiology of Disease Oct 2023Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's disease (AD) and preclinical models. The brain regions where IIS are largest are...
Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's disease (AD) and preclinical models. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked which areas dominate the activity during IIS along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the MS cholinergic neurons selectively would reduce IIS. We used mice that simulate aspects of AD: Tg2576 mice, presenilin 2 (PS2) knockout mice and Ts65Dn mice. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with choline-acetyltransferase (ChAT)-Cre mice and offspring were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs (DREADDs). We recorded local field potentials along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. We detected IIS in all transgenic or knockout mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and occurred primarily during REM sleep. In all 3 mouse lines, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Current source density analysis showed robust and early current sources in the DG, and additional sources in CA1 and the cortex also. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS rate during REM sleep without affecting the overall duration, number of REM bouts, latency to REM sleep, or theta power during REM. Notably, two control interventions showed no effects. Consistent maximal amplitude and strong current sources of IIS in the DG suggest that the DG is remarkably active during IIS. In addition, selectively reducing MS cholinergic tone, at times when MS is hyperactive, could be a new strategy to reduce IIS in AD.
Topics: Mice; Animals; Alzheimer Disease; Cholinergic Neurons; Dentate Gyrus; Cholinergic Agents; Mice, Knockout
PubMed: 37714307
DOI: 10.1016/j.nbd.2023.106294 -
BioRxiv : the Preprint Server For... Aug 2023Alcohol use disorder (AUD) is characterized by excessive alcohol seeking and use. Here, we investigated the molecular correlates of impaired extinction of alcohol...
Alcohol use disorder (AUD) is characterized by excessive alcohol seeking and use. Here, we investigated the molecular correlates of impaired extinction of alcohol seeking using a multidimentional mouse model of AUD. We distinguished AUD-prone and AUD-resistant mice, based on the presence of ≥ 2 or < 2 criteria of AUD and utilized RNA sequencing to identify genes that were differentially expressed in the hippocampus and amygdala of mice meeting ≥ 2 or < 2 criteria, as these brain regions are implicated in alcohol motivation, seeking, consumption and the cognitive inflexibility characteristic of AUD. Our findings revealed dysregulation of the genes associated with the actin cytoskeleton, including actin binding molecule cofilin, and impaired synaptic transmission in the hippocampi of mice meeting ≥ 2 criteria. Overexpression of cofilin in the polymorphic layer of the dentate gyrus (PoDG) inhibited ML-DG synapses, increased motivation to seek alcohol and impaired extinction of alcohol seeking, resembling the phenotype observed in mice meeting ≥ 2 criteria. Overall, our study uncovers a novel mechanism linking increased hippocampal cofilin expression with the AUD phenotype.
PubMed: 37662388
DOI: 10.1101/2023.08.24.554622 -
Frontiers in Neuroscience 2023Experiencing chronic stress significantly increases the risk for depression. Depression is a complex disorder with varied symptoms across patients. However, feeling of...
Experiencing chronic stress significantly increases the risk for depression. Depression is a complex disorder with varied symptoms across patients. However, feeling of sadness and decreased motivation, and diminished feeling of pleasure (anhedonia) appear to be core to most depressive pathology. Odorants are potent signals that serve a critical role in social interactions, avoiding danger, and consummatory behaviors. Diminished quality of olfactory function is associated with negative effects on quality of life leading to and aggravating the symptoms of depression. Odor hedonic value (I like or I dislike this smell) is a dominant feature of olfaction and guides approach or avoidance behavior of the odor source. The neural representation of the hedonic value of odorants is carried by the granule cells in the olfactory bulb, which functions to modulate the cortical relay of olfactory information. The granule cells of the olfactory bulb and those of the dentate gyrus are the two major populations of cells in the adult brain with continued neurogenesis into adulthood. In hippocampus, decreased neurogenesis has been linked to development or maintenance of depression symptoms. Here, we hypothesize that chronic mild stress can alter olfactory hedonics through effects on the olfactory bulb neurogenesis, contributing to the broader anhedonia phenotype in stress-associated depression. To test this, mice were subjected to chronic unpredictable mild stress and then tested on measures of depressive-like behaviors, odor hedonics, and measures of olfactory neurogenesis. Chronic unpredictable mild stress led to a selective effect on odor hedonics, diminishing attraction to pleasant but not unpleasant odorants, an effect that was accompanied by a specific decrease in adult neurogenesis and of the percentage of adult-born cells responding to pleasant odorants in the olfactory bulb.
PubMed: 37600017
DOI: 10.3389/fnins.2023.1224941 -
Aging Cell Sep 2023Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing...
Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing spatial information in the brain and is particularly vulnerable to aging, yet its sparse activity has led to difficulties in assessing changes in this area. Using in vivo two-photon calcium imaging, we compared DG neuronal activity and representations of space in young and aged mice walking on an unfamiliar treadmill. We found that calcium activity was significantly higher and less tuned to location in aged mice, resulting in decreased spatial information encoded in the DG. However, with repeated exposure to the same treadmill, both spatial tuning and information levels in aged mice became similar to young mice, while activity remained elevated. Our results show that spatial representations of novel environments are impaired in the aged hippocampus and gradually improve with increased familiarity. Moreover, while the aged DG is hyperexcitable, this does not disrupt neural representations of familiar environments.
Topics: Mice; Animals; Dentate Gyrus; Calcium; Hippocampus; Neurons; Spatial Memory
PubMed: 37491802
DOI: 10.1111/acel.13924 -
Experimental Neurology Dec 2023Traumatic brain injury leads to cellular and circuit changes in the dentate gyrus, a gateway to hippocampal information processing. Intrinsic granule cell firing...
Traumatic brain injury leads to cellular and circuit changes in the dentate gyrus, a gateway to hippocampal information processing. Intrinsic granule cell firing properties and strong feedback inhibition in the dentate are proposed as critical to its ability to generate unique representation of similar inputs by a process known as pattern separation. Here we evaluate the impact of brain injury on cellular decorrelation of temporally patterned inputs in slices and behavioral discrimination of spatial locations in vivo one week after concussive lateral fluid percussion injury (FPI) in mice. Despite posttraumatic increases in perforant path evoked excitatory drive to granule cells and enhanced ΔFosB labeling, indicating sustained increase in excitability, the reliability of granule cell spiking was not compromised after FPI. Although granule cells continued to effectively decorrelate output spike trains recorded in response to similar temporally patterned input sets after FPI, their ability to decorrelate highly similar input patterns was reduced. In parallel, encoding of similar spatial locations in a novel object location task that involves the dentate inhibitory circuits was impaired one week after FPI. Injury induced changes in pattern separation were accompanied by loss of somatostatin expressing inhibitory neurons in the hilus. Together, these data suggest that the early posttraumatic changes in the dentate circuit undermine dentate circuit decorrelation of temporal input patterns as well as behavioral discrimination of similar spatial locations, both of which could contribute to deficits in episodic memory.
Topics: Mice; Animals; Dentate Gyrus; Reproducibility of Results; Hippocampus; Neurons; Brain Injuries
PubMed: 37858696
DOI: 10.1016/j.expneurol.2023.114578 -
Research Square Jul 2023Cognitive decline in Alzheimer's disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, in part via...
BACKGROUND
Cognitive decline in Alzheimer's disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EV). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that tau expression triggers an elevation in brain ceramides and nSMase2 activity.
METHODS
To determine the therapeutic benefit of inhibiting this elevation, we evaluated the efficacy of PDDC, the first potent, selective, orally bioavailable, and brain-penetrable nSMase2 inhibitor, in the PS19 tau transgenic AD murine model. Changes in brain ceramide and sphingomyelin levels, Tau content, histopathology, and nSMase2 target engagement were monitored, as well as changes in the number of brain-derived EVs in plasma and their Tau content. Additionally, we evaluated the ability of PDDC to impede tau propagation in a murine model where an adeno-associated virus(AAV) encoding for P301L/S320F double mutant human tau was stereotaxically-injected unilaterally into the hippocampus and the contralateral transfer to the dentate gyrus was monitored.
RESULTS
Similar to human AD, PS19 mice exhibited increased brain ceramides and nSMase2 activity; both were completely normalized by PDDC treatment. PS19 mice exhibited elevated tau immunostaining, thinning of hippocampal neuronal cell layers, increased mossy fiber synaptophysin immunostaining, and glial activation, all pathologic features of human AD. PDDC treatment significantly attenuated these aberrant changes. Mouse plasma isolated from PDDC-treated PS19 mice exhibited reduced levels of neuron- and microglia-derived EVs, the former carrying lower phosphorylated Tau(pTau) levels, compared to untreated mice. In the AAV tau propagation model, PDDC normalized the tau-induced increase in brain ceramides and significantly decreased tau spreading to the contralateral side.
CONCLUSIONS
PDDC is a first-in-class therapeutic candidate that normalizes elevated brain ceramides and nSMase2 activity leading to the slowing of tau spread in AD mice.
PubMed: 37502930
DOI: 10.21203/rs.3.rs-3131295/v1 -
BioRxiv : the Preprint Server For... Mar 2024The neurosphere assay is the gold standard for determining proliferative and differentiation potential of neural progenitor cells (NPCs) in neurogenesis studies . While...
The neurosphere assay is the gold standard for determining proliferative and differentiation potential of neural progenitor cells (NPCs) in neurogenesis studies . While several assays have been developed to model the process of neurogenesis, they have predominantly used embryonic and early postnatal NPCs derived from the dentate gyrus (DG). A limitation of these approaches is that they do not provide insight into adult-born NPCs, which are modeled to affect hippocampal function and diseases later in life. Here, we show a novel free-floating neurosphere culture system using NPCs isolated from the DG of mature adult and aged mice. The protocol outlines detailed steps on the isolation, propagation, and maintenance of neurospheres from adult and aged (>12 months old) mouse brain and how to differentiate cultured neurospheres into neurons and astrocytes. Culturing adult and aged NPCs provides an important model to (1) investigate cellular and molecular properties of this unique cell population and (2) expand the understanding of plasticity in the adult and aging brain. This protocol requires ∼2 hours to complete dissection, dissociation and culture plating, while differentiation to neuronal and astrocytic lineages takes 9 days. By focusing on neurospheres obtained from animals at later ages this model facilitates investigation of important biological questions related to development and differentiation of hippocampal neurons generated throughout adult life.
PubMed: 38559117
DOI: 10.1101/2024.03.16.585365