Opioid drugs are widely used as analgesics but cause respiratory depression, a potentially lethal side-effect with overdose, by acting on µ-opioid receptors (MORs) expressed in brainstem regions involved in the control of breathing. Although many brainstem regions have been shown to regulate opioid-induced respiratory depression, the types of neurons involved have not been identified. Somatostatin is a major neuropeptide found in brainstem circuits regulating breathing, but it is unknown whether somatostatin-expressing circuits regulate respiratory depression by opioids. We examined the co-expression of Sst (gene encoding somatostatin) and Oprm1 (gene encoding MORs) mRNAs in brainstem regions involved in respiratory depression. Interestingly, Oprm1 mRNA expression was found in the majority (> 50%) of Sst -expressing cells in the preBötzinger Complex, the nucleus tractus solitarius, the nucleus ambiguus, and the Kölliker-Fuse nucleus. We then compared respiratory responses to fentanyl between wild-type and ...

The impact of alcohol abuse on Alzheimer’s disease (AD) is poorly understood. Here, we show that the onset of neurocognitive impairment in a mouse model of AD is hastened by repeated alcohol intoxication through exposure to alcohol vapor, and we provide a comprehensive gene expression dataset of the prefrontal cortex by the single-nucleus RNA sequencing of 113,242 cells. We observed a broad dysregulation of gene expression that involves neuronal excitability, neurodegeneration, and inflammation, including interferon genes. Several genes previously associated with AD in humans by genome-wide association studies were differentially regulated in specific neuronal populations. Gene expression patterns of AD mice with a history of alcohol intoxication were more similar to gene expression signatures of older AD mice with more advanced disease and cognitive impairment than those of younger AD mice with prodromic disease, suggesting that alcohol promotes transcriptional changes consistent with AD progression. Our ...

Interoception, the representation of the body’s internal state, serves as a foundation for emotion, motivation, and wellbeing. Yet despite its centrality in human experience, the neural mechanisms of interoceptive attention are poorly understood. The Interoceptive/Exteroceptive Attention Task (IEAT) is a novel neuroimaging paradigm that compares behavioral tracking of the respiratory cycle (Active Interoception) to tracking of a visual stimulus (Active Exteroception). Twenty-two healthy participants completed the IEAT during two separate scanning sessions ( N  = 44) as part of a randomized control trial of mindful awareness in body-oriented therapy (MABT). Compared with Active Exteroception, Active Interoception deactivated somatomotor and prefrontal regions. Greater self-reported interoceptive sensibility (MAIA scale) predicted sparing from deactivation within the anterior cingulate cortex (ACC) and left-lateralized language regions. The right insula, typically described as a primary interoceptive cortex,...

During the embryonic period, neuronal communication starts before the establishment of the synapses with alternative forms of neuronal excitability, called here embryonic neural excitability (ENE). ENE has been shown to modulate the unfolding of development transcriptional programs, but the global consequences for developing organisms are not all understood. Here, we monitored calcium (Ca2+) transients in the telencephalon of zebrafish embryos as a proxy for ENE to assess the efficacy of transient pharmacological treatments to either increase or decrease ENE. Increasing or decreasing ENE at the end of the embryonic period promoted an increase or a decrease in the numbers of dopamine (DA) neurons, respectively. This plasticity of dopaminergic specification occurs in the subpallium (SP) of zebrafish larvae at 6 d postfertilization (dpf), within a relatively stable population of vMAT2-positive cells. Nondopaminergic vMAT2-positive cells hence constitute an unanticipated biological marker for a reserve pool of...

Spinal sensorimotor circuits interact with supraspinal and peripheral inputs to generate quadrupedal locomotion. Ascending and descending spinal pathways ensure coordination between the forelimbs and hindlimbs. Spinal cord injury (SCI) disrupts these pathways. To investigate the control of interlimb coordination and hindlimb locomotor recovery, we performed two lateral thoracic hemisections on opposite sides of the cord (right T5–T6 and left T10–T11) at an interval of approximately two months in eight adult cats. In three cats, the spinal cord was transected at T12–T13. We collected electromyography (EMG) and kinematic data during quadrupedal and hindlimb-only locomotion before and after spinal lesions. We show that (1) cats spontaneously recover quadrupedal locomotion following staggered hemisections but require balance assistance after the second one, (2) coordination between the forelimbs and hindlimbs displays 2:1 patterns (two cycles of one forelimb within one hindlimb cycle) and becomes weaker and mo...

Peripheral administration of tissue inhibitor of metalloproteinases 2 (TIMP2), a protein inhibitor of matrix metalloproteinases (MMPs), has previously been shown to have beneficial effects on cognition and neurons in aged mice. Here, to better understand the potential of recombinant TIMP2 proteins, an IgG4Fc fusion protein (TIMP2-hIgG4) was developed to extend the plasma half-life of TIMP2. Following one month of administration of TIMP2 or TIMP2-hIgG4 via intraperitoneal injections, 23-month-old male C57BL/6J mice showed improved hippocampal-dependent memory in a Y-maze, increased hippocampal cfos gene expression, and increased excitatory synapse density in the CA1 and dentate gyrus (DG) of the hippocampus. Thus, fusion to hIgG4 extended the half-life of TIMP2 while retaining the beneficial cognitive and neuronal effects. Moreover, it retained its ability to cross the blood-brain barrier. To deepen the mechanistic understanding of the beneficial function of TIMP2 on neuronal activity and cognition, a TIMP2...

Chronic nicotine results in dependence with withdrawal symptoms on discontinuation of use, through desensitization of nicotinic acetylcholine receptors and altered cholinergic neurotransmission. Nicotine withdrawal is associated with increased whole-brain functional connectivity and decreased network modularity; however, the role of cholinergic neurons in those changes is unknown. To identify the contribution of nicotinic receptors and cholinergic regions to changes in the functional network, we analyzed the contribution of the main cholinergic regions to brain-wide activation of the immediate early-gene Fos during withdrawal in male mice and correlated these changes with the expression of nicotinic receptor mRNA throughout the brain. We show that the main functional connectivity modules included the main long-range cholinergic regions, which were highly synchronized with the rest of the brain. However, despite this hyperconnectivity, they were organized into two anticorrelated networks that were separated...

The fruit fly Drosophila melanogaster has provided important insights into how sensory information is transduced by transient receptor potential (TRP) channels in the peripheral nervous system (PNS). However, TRP channels alone have not been able to completely model mechanosensitive transduction in mechanoreceptive chordotonal neurons (CNs). Here, we show that, in addition to TRP channels, the sole voltage-gated sodium channel (NaV) in Drosophila , Para, is localized to the dendrites of CNs. Para is localized to the distal tip of the dendrites in all CNs, from embryos to adults, and is colocalized with the mechanosensitive TRP channels No mechanoreceptor potential C (NompC) and Inactive/Nanchung (Iav/Nan). Para localization also demarcates spike initiation zones (SIZs) in axons and the dendritic localization of Para is indicative of a likely dendritic SIZ in fly CNs. Para is not present in the dendrites of other peripheral sensory neurons. In both multipolar and bipolar neurons in the PNS, Para is present ...

Lateralization of hippocampal function is indicated by varied outcomes of patients with neurologic disorders that selectively affect one hemisphere of this structure, such as temporal lobe epilepsy (TLE). The intrahippocampal kainic acid (IHKA) injection model of TLE allows for targeted damage to the left or right hippocampus, enabling systematic comparison of effects of left-right asymmetry on seizure and nonseizure outcomes. Although varying nonseizure phenotypic outcomes based on injection side in dorsal hippocampus were recently evaluated in this model, differences in chronic seizure patterns in left- (IHKA-L) versus right-injected (IHKA-R) IHKA animals have yet to be evaluated. Here, we assessed hippocampal seizure incidence in male and female IHKA-L and IHKA-R mice. Females displayed increased electrographic seizure activity compared with males at both two and four months postinjection. In addition, IHKA-L females showed higher seizure frequency than IHKA-R on diestrus and estrus at two months postin...

The midbrain periaqueductal gray (PAG), particularly its ventrolateral column (vlPAG), is part of a key descending pathway that modulates nociception, fear and anxiety behaviors in both humans and rodents. It has been previously demonstrated that inhibitory GABAergic neurons within the vlPAG have a major role in this nociceptive modulation. However, the PAG contains a diverse range of neuronal subtypes and the contribution of different subtypes of inhibitory neurons to nociceptive control has not been investigated. Here, we employed a chemogenetic strategy in mice that express Cre recombinase under the promotor for the glycine transporter 2 (GlyT2::cre) to modulate a novel group of glycinergic neurons within the vlPAG and then investigate their role in nociceptive control. We show that activation of GlyT2-PAG neurons enhances cold and noxious heat responses and increases locomotor activity (LMA) in both male and female mice. In contrast, inhibition of GlyT2-PAG neurons reduced nociceptive responses, while ...