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The function of B cells in Alzheimer’s disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (Aβ) may interfere with plaque formation and hence progression of the disease, B cells may contribute beyond merely producing immunoglobulins. Here we show that AD is associated with accumulation of activated B cells in circulation, and with infiltration of B cells into the brain parenchyma, resulting in immunoglobulin deposits around Aβ plaques. Using three different murine transgenic models, we provide counterintuitive evidence that the AD progression requires B cells. Despite expression of the AD-fostering transgenes, the loss of B cells alone is sufficient to reduce Aβ plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGFβ + microglia, respectively. Moreover, therapeutic depletion of B cells at the onset of the disease retards AD progression in mice, suggesting that targeting B cells may also benefit AD patients. Alzheimer’s disease is characterized by progressive dementia and amyloid beta plaque deposition. Here the authors show in three relevant transgenic animal models that accumulation of activated B cells is central to AD pathology and depletion of B cells interferes with both histological and behavioural manifestations of the disease.

Brain stimulation has identified two central subsets of stimulation sites with motivational relevance. First, there is a large and disperse set of sites where stimulation is reinforcing, increasing the frequency of the responses it follows, and second, a much more restricted set of sites where--along with reinforcement--stimulation also has drive-like effects, instigating feeding, copulation, predation, and other motivated acts in otherwise sated or peaceful animals. From this work a dispersed but synaptically interconnected network of reinforcement circuitry is emerging: it includes afferents to the ventral tegmental area and substantia nigra; the dopamine systems themselves; glutamatergic afferents to the striatum; and one of two dopamine-receptor-expressing efferent pathways of the striatum. Stimulation of a limited subset of these sites, including descending inhibitory medial forebrain bundle fibers, induces both feeding and reinforcement, and suggests the possibility of a subset of fibers where stimulation has both drive-like and reinforcing effects. This review stresses the common findings of sites and connectivity between electrical and optogenetic studies of core drive and reinforcement sites. By doing so, it suggests the biological importance of optogenetic follow-up of less-publicized electrical stimulation findings. Such studies promise not only information about origins, neurotransmitters, and connectivity of related networks, by covering more sensory and at least one putative motor component they also promote a much deeper understanding of the breadth of motivational function.

Inputs to midbrain dopamine neurons control rewarding and drug-related behaviors. The authors found that nucleus accumbens inputs and local GABA neurons inhibit dopamine neurons through distinct populations of GABA receptors. Furthermore, genetic deletion of GABA B receptors from dopamine neurons selectively increased behavioral sensitivity to cocaine. Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABA B receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABA B receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.

To systematically understand age-induced molecular changes, we performed spatial transcriptomics of young, middle-aged, and old mouse brains and identified seven transcriptionally distinct regions. All regions exhibited age-associated upregulation of inflammatory mRNAs and downregulation of mRNAs related to synaptic function. Notably, aging white matter fiber tracts showed the most prominent changes with pronounced effects in females. The inflammatory signatures indicated major ongoing events: microglia activation, astrogliosis, complement activation, and myeloid cell infiltration. Immunofluorescence and quantitative MRI analyses confirmed physical interaction of activated microglia with fiber tracts and concomitant reduction of myelin in old mice. In silico analyses identified potential transcription factors influencing these changes. Our study provides a resourceful dataset of spatially resolved transcriptomic features in the naturally aging murine brain encompassing three age groups and both sexes. The results link previous disjointed findings and provide a comprehensive overview of brain aging identifying fiber tracts as a focal point of inflammation. This study profiles the spatial transcriptomic landscape of mouse brain coronal sections across three age groups and both sexes. Here, authors show a strong female-biased pro-inflammatory gene signature in white matter fiber tracts.

Synapse dysfunction is tightly linked to cognitive changes during aging. Emerging evidence suggests that microglia and the extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the brain ECM, and its relationship with microglia, synapses, and cognition during aging remains virtually unexplored. In this study we combine ECM-optimized proteomic workflows with histological analyses in aging mice and discover regional differences in ECM composition and aging-induced ECM remodeling across basal ganglia nuclei. Moreover, we combine two distinct behavioral classification strategies with fixed-tissue confocal imaging and proteomic analysis and identify relationships between the hyaluronan- and proteoglycan-rich ECM and cognitive aging phenotypes. Finally, we provide evidence that aging midbrain microglia lose capacity to interact with and regulate the ECM, and that these aging-associated microglial changes are accompanied by local ECM accumulation and worse behavioral performance. Together, these observations indicate that changing microglia-ECM-synapse interactions contribute to cognitive functioning during healthy aging. Synapse dysfunction contributes to cognitive decline with age. Here, the authors show that aging-related changes in microglia and the extracellular matrix are associated with synapse abundance, extracellular matrix buildup, and cognitive deficits in aging mice.

Short telomeres induce a DNA damage response (DDR) that evokes apoptosis and senescence in human cells. An extant question is the contribution of telomere dysfunction-induced DDR to the phenotypes observed in aging and telomere biology disorders. One candidate is RAP1, a telomere-associated protein that also controls transcription at extratelomeric regions. To distinguish these roles, we generated a knockin mouse carrying a mutated Rap1 , which was incapable of binding telomeres and did not result in eroded telomeres or a DDR. Primary Rap1 knockin embryonic fibroblasts showed decreased RAP1 expression and re-localization away from telomeres, with an increased cytosolic distribution akin to that observed in human fibroblasts undergoing telomere erosion. Rap1 knockin mice were viable, but exhibited transcriptomic alterations, proinflammatory cytokine/chemokine signaling, reduced lifespan, and decreased healthspan with increased body weight/fasting blood glucose levels, spontaneous tumor incidence, and behavioral deficits. Taken together, our data present mechanisms distinct from telomere-induced DDR that underlie age-related phenotypes.

Electrical or optogenetic stimulation of lateral hypothalamic (LH) GABA neurons induces rapid vigorous eating in sated animals. The dopamine system has been implicated in the regulation of feeding. Previous work has suggested that a subset of LH GABA neurons projects to the ventral tegmental area (VTA) and targets GABA neurons, inhibiting them and thereby disinhibiting dopaminergic activity and release. Furthermore, stimulation-induced eating is attenuated by dopamine lesions or receptor antagonists. Here we explored the involvement of dopamine in LH stimulation-induced eating. LH stimulation caused sated mice to pick up pellets of standard chow with latencies that varied based on stimulation intensity; once food was picked up, animals ate for the remainder of the 60-s stimulation period. However, lesion of VTA GABA neurons failed to disrupt this effect. Moreover, direct stimulation of VTA or substantia nigra dopamine cell bodies failed to induce food approach or eating. Looking further, we found that some LH GABA fibers pass through the VTA to more caudal sites, where they synapse onto neurons near the locus coeruleus (LC). Similar eating was induced by stimulation of LH GABA terminals or GABA cell bodies in this peri-LC region. Lesion of peri-LC GABA neurons blocked LH stimulation-induced eating, establishing them as a critical downstream circuit element for LH neurons. Surprisingly, lesions did not alter body weight, suggesting that this system is not involved in the hunger or satiety mechanisms that govern normal feeding. Thus, we present a characterization of brain circuitry that may promote overeating and contribute to obesity.

Robust biomarkers of aging have been developed from DNA methylation in humans and more recently, in mice. This study aimed to generate a novel epigenetic clock in rats—a model with unique physical, physiological, and biochemical advantages—by incorporating behavioral data, unsupervised machine learning, and network analysis to identify epigenetic signals that not only track with age, but also relates to phenotypic aging. Reduced representation bisulfite sequencing (RRBS) data was used to train an epigenetic age (DNAmAge) measure in Fischer 344 CDF (F344) rats. This measure correlated with age at (r = 0.93) in an independent sample, and related to physical functioning (p=5.9e-3), after adjusting for age and cell counts. DNAmAge was also found to correlate with age in male C57BL/6 mice (r = 0.79), and was decreased in response to caloric restriction. Our signatures driven by CpGs in intergenic regions that showed substantial overlap with H3K9me3, H3K27me3, and E2F1 transcriptional factor binding.

A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson’s disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.

Olfactory dysfunction is a prevalent symptom and an early marker of age‐related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's Diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age‐related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice. Our results showed that selective loss of odor discrimination was the earliest smelling behavioral change with aging, followed by a decline in odor sensitivity and detection while odor habituation remained in old mice. Compared to behavioral changes related with cognitive and motor functions, smelling loss was among the earliest biomarkers of aging. During aging, metabolites related with oxidative stress, osmolytes, and infection became dysregulated in the olfactory bulb, and G protein coupled receptor‐related signaling was significantly down regulated in olfactory bulbs of aged mice. Poly ADP‐ribosylation levels, protein expression of DNA damage markers, and inflammation increased significantly in the olfactory bulb of older mice. Lower NAD+ levels were also detected. Supplementation of NAD+ through NR in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health. In the present study, the smelling loss of C57BL/6J mice during non‐pathological aging was systematically characterized. Our data showed that smelling changes were among the earliest changed behaviors during aging. Metabolites related with oxidative stress, osmolytes, and infection were dysregulated in brain regions related with olfaction. DNA damage markers, inflammation, and glial activation increased significantly in OBs of older mice, which together contributed to olfaction decline. Supplementation of NAD+ improved longevity and partially enhanced olfaction in aged mice.