Biology subjects

Kollman, G. J.

Publications and source records attributed to Kollman, G. J..

3 recordsLinked to original sources

bioRxiv2025

Ventral Pallidum GABA Neuron Inhibition Augments Context-Appropriate Defensive Responses to Learned Threat Cues

The ventral pallidum (VP) is embedded within the brain circuits controlling motivated behavior, which are heavily implicated in addiction and other psychiatric disorders. Prior work showed that VP GABAergic neurons (VPGABA) promote reward approach and seeking, while the intermixed population of VP glutamate neurons instead promote avoidance and aversion. Some have thus suggested a functional dichotomy between these VP subpopulations in reward versus threat. We test this hypothesis by asking how inhibiting VPGABA impacts active and passive defensive responses to learned threat cues in the absence of rewards. We taught GAD1:Cre rats with inhibitory VPGABA DREADDs (or control rats) that a metal probe delivers shock, or that a 20sec auditory cue precedes footshocks. These stimuli thereafter elicit active defensive burying, or passive freezing responses, respectively. We found that VPGABA inhibition with CNO markedly increased stimulus-appropriate defensive responses to both types of learned threats, but failed to consistently alter new learning about them--suggesting VPGABA mediates aversive motivation but not memory formation. VPGABA inhibition also altered threat-related c-Fos expression within VP cell populations, and in their efferent target lateral habenula, but not mediodorsal thalamus--pointing to potential underlying circuit mechanisms of defensive responses. Results indicate that VPGABA neurons not only promote reward seeking as previously reported, but that they may also actively inhibit defensive responses to threats that might otherwise compete with reward seeking. This refines our understanding of subcortical valanced motivation circuits, and may suggest new targets for intervening in disorders like addiction and depression. Highlights-Inhibiting VPGABA increases defenses against threatening stimuli -Both active (burying) and passive (freezing) responses were enhanced -Inhibiting VPGABA excites other VP cells, and neurons in downstream LHb -VP subpopulations may interact to bidirectionally modulate circuits and adaptive behaviors Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/672918v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1978f03org.highwire.dtl.DTLVardef@12e4d59org.highwire.dtl.DTLVardef@d81bfforg.highwire.dtl.DTLVardef@164261_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Parkinson's disease-vulnerable and -resilient dopamine neurons display opposite responses to excitatory input

Dopamine (DA) neurons of the substantia nigra (SN) are essential for motor control and selectively degenerate in Parkinsons disease (PD). However, DA neurons are molecularly heterogeneous, with some showing greater vulnerability and others resilience. Here, we show that the DA subtype marker Anxa1, identified in mice, labels PD-vulnerable DA neurons in human SN. Using mice, we found that excitatory inputs from subthalamic (STN) and pedunculopontine (PPN) nuclei evoked frequency-dependent excitation in SN GABA neurons, but complex multiphasic DA neuron responses, suggesting heterogeneous DA subtype responses. Indeed, excitatory inputs evoked differential DA responses in striatal subregions, an increase in caudal striatum, but inhibition followed by rebound in dorsolateral striatum. Additionally, PD-resilient Vglut2+ DA neurons were excited by STN/PPN input, while vulnerable Anxa1+ DA neurons were inhibited. These findings demonstrate that DA subtypes are embedded in distinct functional networks, suggesting that some therapeutic interventions may differentially impact vulnerable and resilient DA subtypes.

neuroscience↗

bioRxiv2024

Ventral tegmental area interneurons revisited: GABA and glutamate projection neurons make local synapses

The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction. Significance statementGABA neurons in VTA are key regulators of VTA dopamine neurons and considered central to the mechanisms by which opioids and other drugs of abuse can induce addiction. Conventionally, these VTA GABA neurons are considered interneurons, but GABA projection neurons are also abundant in VTA, and it is unclear if these represent separate populations. We found that several markers enriched in non-dopamine neurons of VTA, including Mu-opioid receptor, are also expressed in projection neurons, and thus are not selective interneuron markers. Moreover, we found that VTA GABA and glutamate projection neurons collateralize within VTA where they make local synapses. These data challenge the notion of a VTA interneuron that synapses only within VTA and suggest that inhibitory projection neurons can serve functions previously attributed to VTA interneurons.

neuroscience↗