Biology subjects

Soden, M. E.

Publications and source records attributed to Soden, M. E..

8 recordsLinked to original sources

bioRxiv2026

Multidimensional control of ingestive behavior by lateral hypothalamic neurotensin neurons

Consumption of food and water is regulated by interactions between neural circuits that govern motivational drive states, arousal, motor activity, and reward signaling, among other factors. Neurons in the lateral hypothalamus that express the neuropeptide neurotensin (LH-Nts neurons) are known to influence many of these elements, but their precise role in regulating specific aspects of ingestive behavior remains unclear. Utilizing a tightly controlled head-fixed task, we find that LH-Nts neurons strongly encode the rate of licking for water and sweet solutions, with weaker modulation of activity by solution identity and restriction state. Silencing LH-Nts neurons reduces water intake but has little direct effect on hunger or satiety. Instead, we find that these neurons impact multiple underlying behavioral components necessary for food consumption, including arousal and engagement with a novel food source, and also influence thermoregulation and metabolism. Together, these data establish tonic activity of LH-Nts neurons as a critical signal supporting exploration and volitional movement, while also delineating a role for these neurons in driving active consumption, particularly of water. Furthermore, quantitative projection mapping revealed widespread innervation of structures linked to thirst, arousal, reward, metabolism, and facial motor control, suggesting that these neurons play an important role coordinating neural circuits governing multiple different aspects of ingestion.

neuroscience↗

bioRxiv2026

Periaqueductal gray neurotensin neurons drive simultaneousthreat response and reinforcement

The periaqueductal gray (PAG) is a midbrain structure known to influence responses to both threat and reward. The PAG sends projections to the ventral tegmental area (VTA), a region critical for regulating motivated behavior via dopamine release. We previously identified a population of VTA-projecting PAG neurons that express the peptide neurotensin (Nts), a potent dopamine neuron activator. Here we find that PAG-Nts neurons co-release glutamate and Nts in the VTA to drive dopamine neuron activation. These neurons are activated by threats and threat-predictive cues and are inhibited by entry into a shelter and during reward consumption. Optogenetic stimulation elicits a robust threat response, including freezing and tail rattle, but remarkably can also drive intracranial self-stimulation. This operant reinforcement behavior is dopamine dependent while the threat response is not. Together, these results identify a dual-output circuit that engages the dopamine system, likely to increase the salience of environmental stimuli, while simultaneously driving specific threat response behaviors.

neuroscience↗

bioRxiv2023

Kappa Opioid Receptors in Mesolimbic Terminals Mediate Escalation of Cocaine Consumption

Increases in drug consumption over time, also known as escalation, is a key behavioral component of substance use disorder (SUD) that is related to potential harm to users, such as overdose. Studying escalation also allows researchers to investigate the transition from casual drug use to more SUD-like drug use. Understanding the neurobiological systems that drive this transition will inform therapeutic treatments in the aim to prevent increases in drug use and the development of SUD. The kappa opioid receptor (KOR) system is typically known for its role in negative affect, which is commonly found in SUD as well. Furthermore, the KOR system has also been implicated in drug use and importantly, modulating the negative effects of drug use. However, the specific neuronal subpopulation expressing KOR involved has not been identified. Here, we first demonstrated that pharmacologically inhibiting KOR in the nucleus accumbens core (NAcC), as a whole, blocks cocaine escalation under long-access self-administration conditions. We then demonstrated that KOR expressed on ventral tegmental area (VTA) neurons but not NAcC neurons is sufficient for blocking cocaine escalation by utilizing a novel virally-mediated CRISPR-SaCas9 knock-out of the oprk1 gene. Together, this suggests that activation of KOR on VTA terminals in the NAcC drives the transition to the SUD-like phenotype of escalation of cocaine consumption.

neuroscience↗

bioRxiv2023

Opto-seq reveals input-specific immediate early gene induction in ventral tegmental area cell types

The ventral tegmental area (VTA) is a critical node in circuits governing motivated behavior and is home to diverse populations of neurons that release dopamine, GABA, glutamate, or combinations of these neurotransmitters. The VTA receives inputs from many brain regions, but a comprehensive understanding of input-specific activation of VTA neuronal subpopulations is lacking. To address this, we combined optogenetic stimulation of select VTA inputs with single-nucleus RNA sequencing (snRNAseq) and highly multiplexed in situ hybridization to identify distinct neuronal clusters and characterize their spatial distribution and activation patterns. Quantification of immediate early gene (IEG) expression revealed that different inputs activated select VTA subpopulations, which demonstrated cell-type specific IEG programs. Within dopaminergic subpopulations IEG induction levels correlated with differential expression of ion channel genes. This new transcriptomics-guided circuit analysis reveals the diversity of VTA activation driven by distinct inputs and provides a resource for future analysis of VTA cell types.

neuroscience↗

bioRxiv2022

A circuit mechanism for the coordinated actions of opposing neuropeptide and neurotransmitter signals

Fast-acting neurotransmitters and slow, modulatory neuropeptides are commonly co-released from neurons in the central nervous system (CNS), albeit from distinct synaptic vesicles1. The mechanisms of how co-released neurotransmitters and neuropeptides that have opposing actions, e.g., stimulatory versus inhibitory, work together to exert control of neural circuit output remain unclear. This question has been difficult to resolve due to the inability to selectively isolate these signaling pathways in a cell- and circuit-specific manner. To overcome these barriers, we developed a genetic-based anatomical disconnect procedure that utilizes distinct DNA recombinases to independently facilitate conditional in vivo CRISPR/Cas9 mutagenesis2 of neurotransmitter- and neuropeptide-related genes in distinct cell types in two different brain regions simultaneously. With this approach we demonstrate that the stimulatory neuropeptide neurotensin (Nts) and the inhibitory neurotransmitter{gamma} -aminobutyric acid (GABA), which are co-released from neurons in the lateral hypothalamus (LH), work coordinately to activate dopamine neurons of the ventral tegmental area (VTA-DA). We show that GABA release from LH-Nts neurons acts on GABA neurons within the VTA to rapidly disinhibit VTA-DA neurons, while Nts signals through the Nts receptor 1 (Ntsr1) on VTA-DA neurons to promote a slow depolarization of these cells. Thus, these two signals act on distinct time scales through different cell types to enhance mesolimbic dopamine neuron activation, which optimizes behavioral reinforcement. These data demonstrate a circuit-based mechanism for the coordinated action of a neurotransmitter and neuropeptide with opposing effects on cell physiology.

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bioRxiv2022

Netrin-1 regulates the balance of glutamatergic connectivity in the adult ventral tegmental area

The axonal guidance cue netrin-1 serves a critical role in neural circuit development by promoting growth cone motility, axonal branching, and synaptogenesis. Within the adult mouse brain, expression of the gene encoding netrin-1 (Ntn1) is highly enriched in the ventral midbrain where it is expressed in both GABAergic and dopaminergic neurons, but its function in these cell types in the adult system remains largely unknown. To address this, we performed viral-mediated, cell-type specific CRISPR-Cas9 mutagenesis of Ntn1 in the ventral tegmental area (VTA) of adult mice. Ntn1 loss-of-function in either cell type resulted in a significant reduction in excitatory postsynaptic connectivity. In dopamine neurons, reduced excitatory tone had a minimal phenotypic behavioral outcome; however, reduced glutamatergic tone on VTA GABA neurons induced behaviors associated with a hyperdopaminergic phenotype. Loss of Ntn1 function in both cell types simultaneously largely rescued the phenotype observed in the GABA-only mutagenesis. These findings demonstrate an important role for netrin-1 in maintaining excitatory connectivity in the adult midbrain and that a balance in this connectivity within two of the major cell types of the VTA is critical for the proper functioning of the mesolimbic system.

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bioRxiv2021

Intrinsic regulators of the action potential waveform control dopamine release to shape behavior

Despite the widely known role of dopamine in reinforcement learning, how the patterns of dopamine release that are critical to the acquisition, performance, and extinction of conditioned responses are generated is poorly resolved. Here, we demonstrate that the coordinated actions of two ion channels, Kv4.3 and BKCa1.1, control the pattern of dopamine neuron firing and dopamine release on different time scales to regulate separate phases of reinforced behavior in mice. Inactivation of Kv4.3 in VTA dopamine neurons increases ex vivo pacemaker activity and excitability that is associated with increased in vivo ramping dynamics prior to lever press in a learned instrumental response paradigm. Loss of Kv4.3 enhances performance of the learned response and facilitates extinction. In contrast, loss of BKCa1.1 increases burst firing and phasic dopamine release that enhances learning of an instrumental response. Inactivation of BKCa1.1 enhances extinction burst lever pressing in early extinction training that is associated with increased reward prediction error signals. These data demonstrate that temporally distinct patterns of dopamine release are governed by the intrinsic regulators of the cell to shape behavior. TeaserWe show that ion channels in midbrain dopamine neurons are critical for patterning action potential firing at the cell body and governing neurotransmitter release to regulate reinforcement learning.

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bioRxiv2020

A midbrain dynorphin circuit promotes threat generalization

Discrimination between predictive and non-predictive threat stimuli decrease as threat intensity increases. The central mechanisms that mediate the transition from discriminatory to generalized threat responding remain poorly resolved. Here, we identify the stress- and dysphoria-associated kappa opioid receptor (KOR) and its ligand dynorphin (Dyn), acting in the ventral tegmental area (VTA), as a key substrate for regulating threat generalization. We identified several dynorphinergic inputs to the VTA and demonstrate that projections from the bed nucleus of the stria terminalis (BNST) and dorsal raphe nucleus (DRN) both contribute to anxiety-like behavior but differentially affect threat generalization. These data demonstrate that conditioned threat discrimination has an inverted U relationship with threat intensity and establish a role for KOR/Dyn signaling in the midbrain for promoting threat generalization.

neuroscience↗