Biology subjects

Baertsch, N. A.

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

7 recordsLinked to original sources

bioRxiv2026

A projection atlas of excitatory and inhibitory inputs to the preBötzinger Complex: substrates for multimodal breathing control

Breathing is an essential motor behavior that emerges from the activity of rhythm-generating neurons in the preBotzinger Complex (preBotC). Although the properties of preBotC neurons are sufficient for rhythmogenesis, their activity is continually shaped by long-range inputs that convey homeostatic, emotional, volitional, and behavioral influences. Here, we provide a systematic survey of monosynaptic projections from excitatory (glutamatergic) and inhibitory (GABAergic) neurons across the mouse brain that target the preBotC. Using a dual recombinase-dependent retrograde tracing approach, we compile an atlas of afferent regions, highlighting the breadth of excitatory and inhibitory inputs that converge on this critical network. This atlas underscores the preBotC as a nexus where multimodal signals are integrated to regulate rhythm generation and patterning. Rather than a self-contained oscillator, the preBotC is a hub whose function is tuned by diverse long-range excitatory and inhibitory influences. By defining the anatomical substrates of this input, we lay a foundation for dissecting the functional roles of higher-order brain regions in shaping breathing across physiological, behavioral, and pathological contexts. SIGNIFICANCE STATEMENTBreathing is controlled by a small brainstem region called the preBotzinger Complex, which generates the rhythm for each breath. Many other brain areas influence this region, but the sources of these inputs--and whether they excite or inhibit breathing--have not been systematically mapped. Here, we present a detailed anatomical atlas identifying where excitatory and inhibitory signals to the preBotzinger Complex arise across the mouse brain. This resource provides a structural framework for understanding how breathing is shaped by sensory signals, behavior, and brain state.

neuroscience↗

bioRxiv2023

Interdependence of cellular and network properties in respiratory rhythmogenesis

How breathing is generated by the preBotzinger Complex (preBotC) remains divided between two ideological frameworks, and the persistent sodium current (INaP) lies at the heart of this debate. Although INaP is widely expressed, the pacemaker hypothesis considers it essential because it endows a small subset of neurons with intrinsic bursting or "pacemaker" activity. In contrast, burstlet theory considers INaP dispensable because rhythm emerges from "pre-inspiratory" spiking activity driven by feed-forward network interactions. Using computational modeling, we discover that changes in spike shape can dissociate INaP from intrinsic bursting. Consistent with many experimental benchmarks, conditional effects on spike shape during simulated changes in oxygenation, development, extracellular potassium, and temperature alter the prevalence of intrinsic bursting and pre-inspiratory spiking without altering the role of INaP. Our results support a unifying hypothesis where INaP and excitatory network interactions, but not intrinsic bursting or pre-inspiratory spiking, are critical interdependent features of preBotC rhythmogenesis. SIGNIFICANCE STATEMENTBreathing is a vital rhythmic process originating from the preBotzinger complex. Since its discovery in 1991, there has been a spirited debate about whether respiratory rhythm generation emerges as a network property or is driven by a subset of specialized neurons with rhythmic bursting capabilities, endowed by intrinsic currents. Here, using computational modeling, we propose a unifying data-driven model of respiratory rhythm generation which bridges the gap between these competing theories. In this model, both intrinsic cellular properties (a persistent sodium current) and network properties (recurrent excitation), but not intrinsic bursting, are essential and interdependent features of respiratory rhythm generation.

neuroscience↗

bioRxiv2023

Modeling effects of variable preBötzinger Complex network topology and cellular properties on opioid-induced respiratory depression and recovery

The pre-Botzinger complex (preBotC), located in the medulla, is the essential rhythm-generating neural network for breathing. The actions of opioids on this network impair its ability to generate robust, rhythmic output, contributing to life-threatening opioid-induced respiratory depression (OIRD). The occurrence of OIRD varies across individuals and internal and external states, increasing the risk of opioid use, yet the mechanisms of this variability are largely unknown. In this study, we utilize a computational model of the preBotC to perform several in silico experiments exploring how differences in network topology and the intrinsic properties of preBotC neurons influence the sensitivity of the network rhythm to opioids. We find that rhythms produced by preBotC networks in silico exhibit variable responses to simulated opioids, similar to the preBotC network in vitro. This variability is primarily due to random differences in network topology and can be manipulated by imposed changes in network connectivity and intrinsic neuronal properties. Our results identify features of the preBotC network that may regulate its susceptibility to opioids. Significance StatementThe neural network in the brainstem that generates the breathing rhythm is disrupted by opioid drugs. However, this response can be surprisingly unpredictable. By constructing computational models of this rhythm-generating network, we illustrate how random differences in the distribution of biophysical properties and connectivity patterns within individual networks can predict their response to opioids, and we show how modulation of these network features can make breathing more susceptible or resistant to the effects of opioids.

neuroscience↗

bioRxiv2021

Leukocyte proliferation mediates disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of Leigh syndrome. Directly depleting leukocytes with a colony-stimulating factor 1 receptor (CSF1R) inhibitor dramatically attenuates disease, including complete prevention of CNS lesion formation and substantial extension of survival. Leukocyte depletion rescues a range of symptoms including hyperlactemia, seizures, respiratory function, and neurologic symptoms. These data provide a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement directly drives disease. These findings have significant implication for the mechanisms of disease resulting from mitochondrial dysfunction, and may lead to novel therapeutic strategies. One-Sentence SummaryPharmacologic targeting of leukocytes prevents CNS lesions, neurological disease, and metabolic dysfunction in the Ndufs4(KO) mouse model of Leigh syndrome.

pathology↗

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↗