Neuroimmunometabolism is an emerging field that examines the intersection of immunological and metabolic cascades in the brain. Neuroinflammatory conditions often involve differential metabolic reprogramming in neuronal and glial cells through their immunometabolic sensors. The impact of such bioenergetic adaptation on general brain function is poorly understood, but this cross-talk becomes increasingly important in neurodegenerative disorders that exhibit reshaping of neuroimmunometabolic pathways. Here we summarize the intrinsic balance of neuroimmunometabolic substrates and sensors in the healthy brain and how their dysregulation can contribute to the pathophysiology of various neurodegenerative disorders. This review also proposes possible avenues for disease management through neuroimmunometabolic profiling and therapeutics to bridge translational gaps and guide future treatment strategies. SIGNIFICANCE STATEMENT Neuroimmunometabolism intersects with neuroinflammation and immunometabolic regulation...

The axon initial segment, nodes of Ranvier, and the oligodendrocyte-derived myelin sheath have significant influence on the firing patterns of neurons and the faithful, coordinated transmission of action potentials to downstream brain regions. In the olfactory bulb, olfactory discrimination tasks lead to adaptive changes in cell firing patterns, and the output signals must reliably travel large distances to other brain regions along highly myelinated tracts. Whether myelinated axons adapt to facilitate olfactory sensory processing is unknown. Here, we investigate the morphology and physiology of mitral cell axons in the olfactory system of adult male and female mice and show that unilateral sensory deprivation causes system-wide adaptations in axonal morphology and myelin thickness. Mitral cell spiking patterns and action potentials also adapted to sensory deprivation. Strikingly, myelination, and mitral cell physiology were altered on both the deprived and non-deprived sides, indicating system level adapt...

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 posttraining nap, slow-wave activity (SWA) and sigma activity during 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 tra...

Neuronal activity in the prefrontal cortex (PFC) controls dominance hierarchies in groups of animals. Dopamine (DA) strongly modulates PFC activity mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs). Still, it is unclear how these two subpopulations of DA receptor-expressing neurons in the PFC regulate social dominance hierarchy. Here, we demonstrate distinct roles for prefrontal D1R- and D2R-expressing neurons in establishing social hierarchy, with D1R+ neurons determining dominance and D2R+ neurons for subordinate. Ex vivo whole-cell recordings revealed that the dominant status of male mice correlates with rectifying AMPAR transmission and stronger excitatory synaptic strength onto D1R+ neurons in PFC pyramidal neurons. In contrast, the submissive status is associated with higher neuronal excitability in D2R+ neurons. Moreover, simultaneous manipulations of synaptic efficacy of D1R+ neurons in dominant male mice and neuronal excitability of D2R+ neurons of their male subordinates switch their dom...

Peripheral nerves are organized into discrete compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium, a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a neuropathy with similar defects. Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization in mice of both genders. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs noncanonically (i.e., independent of hedgehog signaling). Gli1 and Dhh also ...

Much animal learning is slow, with cumulative changes in behavior driven by reward prediction errors. When the abstract structure of a problem is known, however, both animals and formal learning models can rapidly attach new items to their roles within this structure, sometimes in a single trial. Frontal cortex is likely to play a key role in this process. To examine information seeking and use in a known problem structure, we trained monkeys in an explore/exploit task, requiring the animal first to test objects for their association with reward, then, once rewarded objects were found, to reselect them on further trials for further rewards. Many cells in the frontal cortex showed an explore/exploit preference aligned with one-shot learning in the monkeys' behavior: the population switched from an explore state to an exploit state after a single trial of learning but partially maintained the explore state if an error indicated that learning had failed. Binary switch from explore to exploit was not explained...

The K+-Cl– cotransporter KCC2, encoded by the Slc12a5 gene, is a neuron-specific chloride extruder that tunes the strength and polarity of GABAA receptor-mediated transmission. In addition to its canonical ion transport function, KCC2 also regulates spinogenesis and excitatory synaptic function through interaction with a variety of molecular partners. KCC2 is enriched in the vicinity of both glutamatergic and GABAergic synapses, the activity of which in turn regulates its membrane stability and function. KCC2 interaction with the submembrane actin cytoskeleton via 4.1N is known to control its anchoring near glutamatergic synapses on dendritic spines. However, the molecular determinants of KCC2 clustering near GABAergic synapses remain unknown. Here, we used proteomics to identify novel KCC2 interacting proteins in the adult rat neocortex. We identified both known and novel candidate KCC2 partners, including some involved in neuronal development and synaptic transmission. These include gephyrin, the main sc...

Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and in vitro studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, ...

Multiciliated ependymal cells line the ventricle wall and generate CSF flow through ciliary beating. Defects in ependymal cells cause hydrocephalus; however, there are still significant gaps in our understanding the molecular, cellular and developmental mechanisms involved in the pathogenesis of hydrocephalus. Here, we demonstrate that specific deletion of RNA-binding protein (RBP) Hu antigen R (HuR) in the mouse brain results in hydrocephalus and causes postnatal death. HuR deficiency leads to impaired ependymal cell development with defective motile ciliogenesis in both female and male mice. Transcriptome-wide analysis reveals that HuR binds to mRNA transcripts related to ciliogenesis, including cilia and flagella associated protein 52 ( Cfap52 ), the effector gene of Foxj-1 and Rfx transcriptional factors. HuR deficiency accelerates the degradation of Cfap52 mRNA, while overexpression of Cfap52 is able to promote the development of HuR-deficient ependymal cells. Taken together, our results unravel the i...