Neuroimmunometabolism is an emerging field that examines the intersection of immunologic 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 of ...

The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer's disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks ( n = 68); (2) longitudinal structural MRI from Alzheimer's disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns ( n = 349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks' vulnerability to amyloid and tau ( n = 186). Our results suggest that the atrophy of distinct MTL subregions ...

Ferroptosis is a caspase-independent, iron-dependent form of regulated necrosis extant in traumatic brain injury, Huntington disease, and hemorrhagic stroke. It can be activated by cystine deprivation leading to glutathione depletion, the insufficiency of the antioxidant glutathione peroxidase-4, and the hemolysis products hemoglobin and hemin. A cardinal feature of ferroptosis is extracellular signal-regulated kinase (ERK)1/2 activation culminating in its translocation to the nucleus. We have previously confirmed that the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor U0126 inhibits persistent ERK1/2 phosphorylation and ferroptosis. Here, we show that hemin exposure, a model of secondary injury in brain hemorrhage and ferroptosis, activated ERK1/2 in mouse neurons. Accordingly, MEK inhibitor U0126 protected against hemin-induced ferroptosis. Unexpectedly, U0126 prevented hemin-induced ferroptosis independent of its ability to inhibit ERK1/2 signaling. In contrast to classical ferroptosis in...

We aimed to investigate a sexually dimorphic role of calcitonin gene-related peptide (CGRP) in rodent models of pain. Based on findings in migraine where CGRP has a preferential pain-promoting effect in female rodents, we hypothesized that CGRP antagonists and antibodies would attenuate pain sensitization more efficaciously in female than male mice and rats. In hyperalgesic priming induced by activation of interleukin 6 signaling, CGRP receptor antagonists olcegepant and CGRP8-37 both given intrathecally, blocked, and reversed hyperalgesic priming only in females. A monoclonal antibody against CGRP, given systemically, blocked priming specifically in female rodents but failed to reverse it. In the spared nerve injury model, there was a transient effect of both CGRP antagonists, given intrathecally, on mechanical hypersensitivity in female mice only. Consistent with these findings, intrathecally applied CGRP caused a long-lasting, dose-dependent mechanical hypersensitivity in female mice but more transient ...

The multiple demand system is a network of fronto-parietal brain regions active during the organisation and control of diverse cognitive operations. It has been argued that this activation may be a non-specific signal of task difficulty. However, here we provide convergent evidence for a causal role for the multiple demand network in the ‘simple task’ of automatic auditory change detection, through the impairment of top-down control mechanisms. We employ independent structure-function mapping, dynamic causal modelling, and frequency-resolved functional connectivity analyses of MRI and MEG from 75 mixed-sex human patients across four neurodegenerative syndromes (bvFTD, nfvPPA, PCA and AD-MCI) and 48 age-matched controls. We show that atrophy of any multiple demand node is sufficient to impair auditory neurophysiological response to change in frequency, location, intensity, continuity or duration. There was no similar association with atrophy of the cingulo-opercular, salience or language networks, or with g...

The presynaptic action potential (AP) is required to drive calcium influx into nerve terminals, resulting in neurotransmitter release. Accordingly, the AP waveform is crucial in determining the timing and strength of synaptic transmission. The calyx of Held nerve terminals of rat of either sex showed minimum changes in AP waveform during high-frequency AP firing. We found that the stability of the calyceal AP waveform requires KCNQ (KV7) K+ channel activation during high-frequency spiking activity. High-frequency presynaptic spikes gradually led to accumulation of KCNQ channels in open states which kept interspike membrane potential sufficiently negative to maintain Na+ channel availability. Blocking KCNQ channels during stimulus trains led to inactivation of presynaptic Na+, and to a lesser extent KV1 channels, thereby reducing the AP height and broadening AP duration. Moreover, blocking KCNQ channels disrupted the stable calcium influx and glutamate release required for reliable synaptic transmission at ...

Neuropathic pain (NP) is one of the most common and debilitating comorbidities of spinal cord injury (SCI). Current therapies are often ineffective due in part to an incomplete understanding of underlying pathogenic mechanisms. In particular, it remains unclear how SCI leads to dysfunction in the excitability of nociceptive circuitry. The immediate early gene c-Fos has long been used in pain processing locations as a marker of neuronal activation. We employed a mouse reporter line with fos-promoter driven Cre-recombinase to define neuronal activity changes in relevant pain circuitry locations following C5/6 contusion (using both females and males), a SCI model that results in multiple forms of persistent NP-related behavior. SCI significantly increased activation of cervical dorsal horn (DH) projection neurons, as well as induced a selective reduction in the activation of a specific DH projection neuron subpopulation that innervates the periaqueductal gray (PAG), an important brain region involved in desce...

Opioid tolerance (OT) leads to dose escalation and serious side effects, including opioid-induced hyperalgesia (OIH). We sought to better understand the mechanisms underlying this event in the gastrointestinal tract. Chronic in vivo administration of morphine by intraperitoneal (i.p.) injection in male C57BL/6 mice evoked tolerance and evidence of OIH in an assay of colonic afferent nerve mechanosensitivity; this was inhibited by the δ-opioid receptor (DOPr) antagonist naltrindole when i.p. injected previous morphine administration. Patch clamp studies of dorsal root ganglia (DRG) neurons following overnight incubation with high concentrations of morphine, the µ-opioid receptors (MOPr) agonist DAMGO or the DOPr agonist DADLE evoked hyperexcitability. The pronociceptive actions of these opioids were blocked by the DOPr antagonist SDM25N but not the MOPr antagonist CTOP. The hyperexcitability induced by DAMGO was reversed after a 1 hr washout but reapplication of low concentrations of DAMGO or DADLE restored...

Traumatic spinal cord injury (SCI) is a leading cause of permanent neurological disabilities in young adults. Functional impairments after SCI are substantially attributed to the progressive neurodegeneration. However, regeneration of spinal specific neurons and circuit re-assembly remain challenging in the dysregulated milieu of SCI due to impaired neurogenesis and neuronal maturation by neural precursor cells (NPCs) spontaneously or in cell-based strategies. The extrinsic mechanisms that regulate neuronal differentiation and synaptogenesis in SCI are poorly understood. Here, we perform extensive in vitro and in vivo studies to unravel that SCI-induced upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) impedes neurogenesis of NPCs through co-activation of two receptor protein tyrosine phosphatases, LAR and PTPσ. In adult female rats with SCI, systemic co-inhibition of LAR and PTPσ promotes regeneration of motoneurons and spinal interneurons by engrafted human directly reprogrammed caudalized...

Synaptic inputs that target distal regions of neuronal dendrites can often generate local dendritic spikes that can amplify synaptic depolarization, induce synaptic plasticity, and enhance neuronal output. However, distal dendritic spikes are subject to significant attenuation by dendritic cable properties, and often produce only a weak subthreshold depolarization of the soma. Nonetheless, such spikes have been implicated in memory storage, sensory perception and place field formation. How can such a weak somatic response produce such powerful behavioral effects? Here we use dual dendritic and somatic recordings in acute hippocampal slices of male mice to reveal that dendritic spike propagation, but not spike initiation, is strongly enhanced when the somatic resting potential is depolarized, likely as a result of increased inactivation of A-type K+ channels. Somatic depolarization also facilitates the induction of a form of dendritic spike driven heterosynaptic plasticity that enhances memory specificity. ...