Biology subjects

Kelz, M. B.

Publications and source records attributed to Kelz, M. B..

6 recordsLinked to original sources

bioRxiv2026

A Novel Conditional Adra2a-Knockout Mouse Line Reveals Cell-specific Contributions to Specific Dimensions of Sedation

IntroductionHere, we create a conditional Adra2a line and use it to show that sedative, hypnotic, and hypothermic effects of 2-agonists are neuronally mediated via the 2A adrenergic receptor. MethodsWe generated mice with loxP sites flanking Adra2a using CRISPR/Cas9 gene targeting. This line was crossed with lines encoding Cre recombinase (Cre) under the control of the Vgat, Snap25, and Dbh promoters. Cell-specific knockout was confirmed using fluorescent in-situ hybridization demonstrating targeted reduction in Adra2a mRNA in the appropriate cell types. Mice were given intraperitoneal dexmedetomidine (0.3 or 1 mg/kg) or saline, and 20 minutes later righting reflex was assessed, followed by 3 rounds of rotarod testing, with fall time and end temperature recorded. Spontaneous activity was recorded using beam break for an hour after. Mice of each genotype were implanted with EEG leads and recorded while given 0.3 mg/kg IP dexmedetomidine. ResultsWe created a conditional knockout and demonstrated cell-type specific reduction of Adra2a mRNA in crossed lines with cell-specific Cre. The pan-neuronal Adra2a knockout showed resistance to all temperature, sedative, and hypnotic effect endpoints in response to the 2-agonist dexmedetomidine. Adrenergic knockout demonstrated resistance to 2-agonist hypnosis and moderate resistance to hypothermia and impaired coordination with forced movement. GABAergic knockout showed resistance only to impairment of spontaneous movement by 2-agonists. Spectral analysis of the EEG showed an increase in proportion of delta power with a sedative dose of dexmedetomidine in all lines except the pan-neuronal Adra2a knockout. DiscussionFuture studies will pursue both the specific subtype(s) and location of neuronal populations responsible for sedative, hypnotic, and hypothermic effects of 2-agonists.

neuroscience↗

bioRxiv2025

Convergent Control of NREM Sleep and Anesthesia by Prefrontal Layer 5 Extratelencephalic Neurons

The cortical mechanisms that actively suppress consciousness remain poorly understood. Here, we identify a specific subset of prefrontal cortical (PFC) neurons that are activated under anesthesia while most cortical neurons are suppressed. Chemogenetic activation of these excitatory neurons enhances anesthetic potency and deepens NREM sleep, whereas their inhibition blunts anesthetic effects and disrupts sleep. We designate these cells NREM- and Anesthesia-Promoting (NAP) neurons. NAP neurons correspond to layer 5 extratelencephalic (L5 ET) neurons enriched in hyperpolarization-activated cyclic nucleotide-gated (HCN1) expression and characteristic HCN-mediated electrophysiological properties. Mechanistically distinct anesthetics act directly and specifically on PFC L5-ET neurons to increase their excitability. NAPs have sparse cortical projections and predominately innervate subcortical targets including anterior and reticular thalamic nuclei. Using a transgenic mouse line (Colgalt2-cre), we confirm that PFC L5 ET neurons are preferentially activated under anesthesia and during deep recovery NREM sleep. Finally, we show that activation of thalamic-projecting Colgalt2-expressing PFC neurons is sufficient to promote deep NREM sleep. These findings identify a novel prefrontal corticothalamic circuit that provides a shared cortical substrate for naturally occurring sleep and anesthetic-induced unconsciousness.

neuroscience↗

bioRxiv2024

Changes in brain connectivity and neurovascular dynamics during dexmedetomidine-induced loss of consciousness

Understanding the neurophysiological changes that occur during loss and recovery of consciousness is a fundamental aim in neuroscience and has marked clinical relevance. Here, we utilize multimodal magnetic resonance neuroimaging to investigate changes in regional network connectivity and neurovascular dynamics as the brain transitions from wakefulness to dexmedetomidine-induced unconsciousness, and finally into early-stage recovery of consciousness. We observed widespread decreases in functional connectivity strength across the whole brain, and targeted increases in structure-function coupling (SFC) across select networks-- especially the cerebellum--as individuals transitioned from wakefulness to hypnosis. We also observed robust decreases in cerebral blood flow (CBF) across the whole brain--especially within the brainstem, thalamus, and cerebellum. Moreover, hypnosis was characterized by significant increases in the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level-dependent signal, localized within visual and somatomotor regions. Critically, when transitioning from hypnosis to the early stages of recovery, functional connectivity strength and SFC--but not CBF--started reverting towards their awake levels, even before behavioral arousal. By further testing for a relationship between connectivity and neurovascular alterations, we observed that during wakefulness, brain regions with higher ALFF displayed lower functional connectivity with the rest of the brain. During hypnosis, brain regions with higher ALFF displayed weaker coupling between structural and functional connectivity. Correspondingly, brain regions with stronger functional connectivity strength during wakefulness showed greater reductions in CBF with the onset of hypnosis. Earlier recovery of consciousness was associated with higher baseline (awake) levels of functional connectivity strength, CBF, and ALFF, as well as female sex. Across our findings, we also highlight the role of the cerebellum as a recurrent marker of connectivity and neurovascular changes between states of consciousness. Collectively, these results demonstrate that induction of, and emergence from dexmedetomidine-induced unconsciousness are characterized by widespread changes in connectivity and neurovascular dynamics.

neuroscience↗

bioRxiv2023

Neural assemblies coordinated by cortical waves are associated with waking and hallucinatory brain states

The relationship between sensory stimuli and perceptions is brain-state dependent: in wakefulness stimuli evoke perceptions; under anesthesia perceptions are abolished; during dreaming and in dissociated states, percepts are internally generated. Here, we exploit this state dependence to identify brain activity associated with internally generated or stimulus-evoked perception. In awake mice, visual stimuli phase reset spontaneous cortical waves to elicit 3-6 Hz feedback traveling waves. These stimulus-evoked waves traverse the cortex and entrain visual and parietal neurons. Under anesthesia and during ketamine-induced dissociation, visual stimuli do not disrupt spontaneous waves. Uniquely in the dissociated state, spontaneous waves traverse the cortex caudally and entrain visual and parietal neurons, akin to stimulus-evoked waves in wakefulness. Thus, coordinated neuronal assemblies orchestrated by traveling cortical waves emerge in states in which perception can manifest. The awake state is privileged in that this coordination is elicited by specifically by external visual stimuli.

neuroscience↗

bioRxiv2021

Visual evoked feedforward-feedback travelling waves organize neural activity across the cortical hierarchy in mice

Sensory processing is distributed among many brain regions that interact via feedforward and feedback signaling. It has been hypothesized that neuronal oscillations mediating feedforward and feedback interactions organize into travelling waves. However, stimulus evoked travelling waves of sufficient spatial scale have never been demonstrated directly. Here, we show that simple visual stimuli reliably evoke two traveling waves with spatial wavelengths that cover much of the cerebral hemisphere in awake mice. 30-50Hz feedforward waves arise in primary visual cortex (V1) and propagate rostrally, while 3-6Hz feedback waves originate in the association cortex and flow caudally. The phase of the feedback wave modulates the amplitude of the feedforward wave and synchronizes firing between V1 and parietal cortex. Altogether, these results provide direct experimental evidence that visual evoked travelling waves percolate through the cerebral cortex and coordinate neuronal activity across broadly distributed networks mediating visual processing.

neuroscience↗

bioRxiv2020

Brain network motifs are markers of loss and recovery of consciousness

Motifs are patterns of inter-connections between nodes of a network, and have been investigated as building blocks of directed networks. This study explored the re-organization of 3-node motifs during loss and recovery of consciousness. Nine healthy subjects underwent a 3-hour anesthetic protocol while 128-channel electroencephalography (EEG) was recorded. In the alpha (8-13 Hz) band, five-minute epochs of EEG were extracted for: baseline; induction; unconscious; 30-, 10- and 5-minutes pre-recovery of responsiveness; 30- and 180-minutes post-recovery of responsiveness. We constructed a functional brain network using the weighted and directed phase lag index, on which we calculated the frequency and topology of 3-node motifs. Three motifs (motifs 1, 2 and 5) were significantly present across participants and epochs, when compared to random networks (p<0.05). The topology of motifs 1 and 5 changed significantly between responsive and unresponsive epochs (p<0.01). Motif 1 was constituted by long-range chain-like connections, while motif 5 was constituted by short-range, loop-like connections. Our results suggest that anesthetic-induced unconsciousness is associated with a topological re-organization of network motifs. As motif topological re-organization may precede (motif 5) or accompany (motif 1) the return of responsiveness, motifs could contribute to the understanding of the neural correlates of consciousness.

neuroscience↗