Cortical layer 1 (L1) contains a diverse population of interneurons which can modulate processing in superficial cortical layers, but the intracortical sources of synaptic input to these neurons, and how these inputs change over development and with sensory experience, is unknown. We here investigated the changing intracortical connectivity to L1 in the primary auditory cortex (A1) of mice of both sexes in in vitro slices across development using laser-scanning photostimulation. Before postnatal day (P)10, L1 cells receive excitatory input from within L1, L2/3, L4, and L5/6 as well as from subplate. Excitatory inputs from all layers increase, especially from L4, and peak during P10-P16, around the peak of the critical period for tonotopy. Inhibitory inputs followed a similar pattern. Functional circuit diversity in L1 emerges after P16. In adults, L1 neurons receive ascending inputs from L2/3 and L5/6, but only few inputs from L4. The transient hyperconnectivity from deep layers but not L2/3 is absent in d...

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...

Adult neural stem cells (NSCs) reside in two distinct niches in the mammalian brain, the ventricular-subventricular zone (V-SVZ) of the forebrain lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. They are thought to be molecularly distinct since V-SVZ NSCs produce inhibitory olfactory bulb (OB) interneurons and SGZ NSCs excitatory dentate granule neurons. Here, we have asked whether this is so by directly comparing V-SVZ and SGZ NSCs from embryogenesis to adulthood using single-cell transcriptional data. We show that the embryonic radial glial precursor (RP) parents of these two NSC populations are very similar, but differentially express a small cohort of genes involved in glutamatergic versus GABAergic neurogenesis. These different RPs then undergo a similar gradual transition to a dormant adult NSC state over the first three postnatal weeks. This dormancy state involves transcriptional shutdown of genes that maintain an active, proliferative, prodifferentiation state an...

Protein hyper-deimination and deficiency of lyso-phospholipids (LPC 18:1) has been associated with the pathology of demyelinating disease in both humans and mice. We uncovered interesting biology of LPC 18:1, in which LPC 18:1 induced optic nerve function restoration through oligodendrocyte maturation and remyelination in mouse model systems. Our in vitro studies show LPC 18:1 protection against neuron-ectopic hyper-deimination and stimulation of oligodendrocyte maturation, while in vivo investigations recorded optic nerve function improvement following optic nerve injections of LPC 18:1, in contrast to LPC 18:0. Thus just a change in a single bond renders a dramatic alternation in biological function. The incorporation of isobaric C13-histidine in newly synthesized myelin proteins and quantitative proteome shifts are consistent with remyelination underlying restoration in optic nerve function. These results suggest that exogenous LPC 18:1 may provide a therapeutic avenue for stemming vision loss in demyel...

A surprising finding of recent studies in mouse is the dominance of widespread movement-related activity throughout the brain, including in early sensory areas. In awake subjects, failing to account for movement risks misattributing movement-related activity to other (e.g., sensory or cognitive) processes. In this article, we 1) review task designs for separating task-related and movement-related activity, 2) review three ‘case studies’ in which not considering movement would have resulted in critically different interpretations of neuronal function, and 3) discuss functional couplings that may prevent us from ever fully isolating sensory, motor, and cognitive-related activity. Our main thesis is that neural signals related to movement are ubiquitous, and therefore ought to be considered first and foremost when attempting to correlate neuronal activity with task-related processes.

Trigeminal neurons convey somatosensory information from craniofacial tissues. In mouse brain, ascending projections from medullary trigeminal neurons arrive at taste neurons in the parabrachial nucleus, suggesting that taste neurons participate in somatosensory processing. However, the cell types that support this convergence were undefined. Using Cre-directed optogenetics and in vivo neurophysiology in anesthetized mice of both sexes, here we studied whether TRPV1-lineage nociceptive and thermosensory fibers are primary neurons that drive trigeminal circuits reaching parabrachial taste cells. We monitored spiking activity in individual parabrachial neurons during photoexcitation of the terminals of TRPV1-lineage fibers arriving at the dorsal trigeminal nucleus caudalis, which relays orofacial somatosensory messages to the parabrachial area. We also recorded parabrachial neural responses to oral delivery of taste, chemesthetic, and thermal stimuli. We found that optical excitation of TRPV1-lineage fibers ...

Temporal coherence of sound fluctuations across spectral channels is thought to aid auditory grouping and scene segregation. Although prior studies on the neural bases of temporal-coherence processing focused mostly on cortical contributions, neurophysiological evidence suggests that temporal-coherence-based scene analysis may start as early as the cochlear nucleus (i.e., the first auditory region supporting cross-channel processing over a wide frequency range). Accordingly, we hypothesized that aspects of temporal-coherence processing that could be realized in early auditory areas may shape speech understanding in noise. We then explored whether physiologically plausible computational models could account for results from a behavioral experiment that measured consonant categorization in different masking conditions. We tested whether within-channel masking of target-speech modulations predicted consonant confusions across the different conditions and whether predictions were improved by adding across-chan...

We previously found that human heroin addicts and mice chronically exposed to morphine exhibit a significant increase in the number of detected hypocretin/orexin (Hcrt)-producing neurons. However, it remains unknown how this increase affects target areas of the hypocretin system involved in opioid withdrawal, including norepinephrine containing structures locus coeruleus (LC) and A1/A2 medullary regions. Using a combination of immunohistochemical, biochemical, imaging, and behavioral techniques, we now show that the increase in detected hypocretin cell number translates into a significant increase in hypocretin innervation and tyrosine hydroxylase (TH) levels in the LC without affecting norepinephrine-containing neuronal cell number. We show that the increase in TH is completely dependent on Hcrt innervation. The A1/A2 regions were unaffected by morphine treatment. Manipulation of the Hcrt system may affect opioid addiction and withdrawal. SIGNIFICANCE STATEMENT Previously, we have shown that the hypothal...

Globally, more than 67 million people are living with the effects of ischemic stroke. Importantly, many stroke survivors develop a chronic inflammatory response that may contribute to cognitive impairment, a common and debilitating sequela of stroke that is insufficiently studied and currently untreatable. 2-Hydroxypropyl-β-cyclodextrin (HPβCD) is an FDA-approved cyclic oligosaccharide that can solubilize and entrap lipophilic substances. The goal of the present study was to determine whether the repeated administration of HPβCD curtails the chronic inflammatory response to stroke by reducing lipid accumulation within stroke infarcts in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we subcutaneously injected young adult and aged male mice with vehicle or HPβCD 3 times per week, with treatment beginning 1 week after stroke. We evaluated mice at 7 weeks following stroke using immunostaining, RNA sequencing, lipidomic, and behavioral analyses. Chronic stroke infarct an...

In humans, age-related declines in vision, hearing, and touch coincide with changes in amplitude and latency of sensory-evoked potentials. These age-related differences in neural activity may be related to a common deterioration of supra-modal brain areas (e.g., PFC) that mediate activity in sensory cortices or reflect specific sensorineural impairments that may differ between sensory modalities. To distinguish between these two possibilities, we measured neuroelectric brain activity while 37 young adults (18-30 years, 18 males) and 35 older adults (60-88 years, 20 males) were presented with a rapid randomized sequence of lateralized auditory, visual, and somatosensory stimuli. Within each sensory domain, we compared amplitudes and latencies of sensory-evoked responses, source activity, and functional connectivity (via phase-locking value) between groups. We found that older adults' early sensory-evoked responses were greater in amplitude than those of young adults in all three modalities, which coincided ...