Biology subjects

Baertsch, N. A.

Publications and source records attributed to Baertsch, N. A..

3 recordsLinked to original sources

bioRxiv2021

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm generating network

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the -opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBotzinger Complex (preB[o]tC). To unravel the cellular- and network-level consequences of MOR activation in the preBotC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBotC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act together to make the normally robust inspiratory-rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.

neuroscience↗

bioRxiv2020

Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons

Parabrachial CGRP neurons receive diverse threat-related signals and contribute to multiple phases of adaptive threat responses, with their inactivation attenuating both unconditioned behavioral responses to somatic pain and fear-memory formation. Because CGRPPBN neurons respond broadly to multi-modal threats, it remains unknown how these distinct adaptive processes are individually engaged. We show that while three partially separable subsets of CGRPPBN neurons broadly collateralize to their respective downstream partners, individual projections accomplish distinct functions: hypothalamic and extended amygdalar projections elicit assorted unconditioned threat responses including autonomic arousal, anxiety, and freezing behavior, while thalamic and basal forebrain projections generate freezing behavior and, unexpectedly, contribute to associative fear learning. Moreover, the unconditioned responses generated by individual projections are complementary, with simultaneous activation of multiple sites driving profound freezing behavior and bradycardia that are not elicited by any individual projection. This semi-parallel, scalable connectivity schema likely contributes to flexible control of threat responses in unpredictable environments.

neuroscience↗

bioRxiv2019

Insights into the dynamic control of breathing revealed through cell-type-specific responses to substance P

The rhythm generating network for breathing must continuously adjust to changing metabolic and behavioral demands. Here, we examine network-based mechanisms in the mouse preB[o]tzinger complex using substance P, a potent excitatory modulator of breathing frequency and stability, as a tool to dissect network properties that underlie dynamic breathing. We find that substance P does not alter the balance of excitation and inhibition during breaths or the duration of the resulting refractory period. Instead, mechanisms of recurrent excitation between breaths are enhanced such that the rate that excitation percolates through the network is increased. Based on our results, we propose a conceptual framework in which three distinct phases, the inspiratory phase, refractory phase, and percolation phase, can be differentially modulated to influence breathing dynamics and stability. Unravelling mechanisms that support this dynamic control may improve our understanding of nervous system disorders that destabilize breathing, many of which are associated with changes in brainstem neuromodulatory systems.

neuroscience↗