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 ...

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 ability to recall something we encounter only once and unexpectedly—for example, that a food type is poisonous—is crucial for survival. Yet, neuroscientific research in recent decades has been dominated by incremental learning paradigms, relatively neglecting how the brain can learn

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 shift in control from dorsomedial to dorsolateral striatum during skill and habit formation has been well established, but whether striatal subregions orchestrate this shift cooperatively or competitively remains unclear. Cortical inputs have also been implicated in the shift toward automaticity, but it is unknown whether they mirror their downstream striatal targets across this transition. We addressed these questions using a five step heterogeneous action sequencing task in male rats that is optimally performed by automated chains of actions. By optimizing automatic habitual responding, we discovered that loss of function in the dorsomedial striatum accelerated sequence acquisition. In contrast, loss of function in the dorsolateral striatum impeded acquisition of sequencing, demonstrating functional opposition within the striatum. Unexpectedly, the mPFC was not involved; however, the lateral orbitofrontal cortex was critical. These results shift current theories about striatal control of behavior to ...

Visual processing is strongly influenced by recent stimulus history, a phenomenon termed adaptation. Prominent theories cast adaptation as a consequence of optimized encoding of visual information by exploiting the temporal statistics of the world. However, this would require the visual system to track the history of individual briefly experienced events, within a stream of visual input, to build up statistical representations over longer timescales. Here, using an openly available dataset from the Allen Brain Observatory, we show that neurons in the early visual cortex of the mouse indeed maintain long-term traces of individual past stimuli that persist despite the presentation of several intervening stimuli, leading to long-term and stimulus-specific adaptation over dozens of seconds. Long-term adaptation was selectively expressed in cortical, but not in thalamic, neurons, which only showed short-term adaptation. Early visual cortex thus maintains concurrent stimulus-specific memory traces of past input,...

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...