Biology subjects

Martin, K. A.

Publications and source records attributed to Martin, K. A..

16 recordsLinked to original sources

bioRxiv2026

Decay chemicals activate a pH-sensing pathway to initiate a persistent state

Animals use multiple sensory systems to identify signs of danger, including dead conspecifics. Fish can identify decaying conspecifics from chemosensory cues, which prompt a long-lasting avoidance; the neural basis of this persistent chemosensory-driven state is not understood. Here, we describe a persistent alarm state in larval zebrafish, where brief exposure to the polyamine decay product, cadaverine, initiates a minutes-long increase in heart rate and suppression of visually-evoked swimming. Cadaverine activates both olfactory and trigeminal neurons, with persistently-active cells in the forebrain and dorsolateral hindbrain. However, we find that cadaverine's persistent effects on hindbrain activity, heart rate, and locomotor suppression are not mediated by olfaction. Instead, they are mediated through trigeminal chemosensation of the basic pH of concentrated cadaverine in solution. Knockout of TrpA1 channels, which are expressed in trigeminal neurons and associated with chemical nociception across species, prevents the persistent suppression of movement from brief exposure to cadaverine. pH-responsive trigeminal neurons project into the dorsolateral hindbrain to mediate persistent activity and long-lasting locomotor suppression through local inhibition. These results demonstrate that non-olfactory chemosensation mediates persistent behavioral responses to death and decay in zebrafish, illustrating how diverse chemosensory systems detect ethologically-relevant cues to drive adaptive behavior.

neuroscience↗

bioRxiv2025

Canonical nuclear envelope protein emerin regulates structure and integrity of the erythrocyte plasma membrane

Red blood cells (RBC) are essential for the survival of aerobic organisms. Mutations in RBC plasma membrane proteins can give rise to a spectrum of diseases characterized by hemolysis, inefficient gas exchange, and anemia. We tested whether emerin (EMD), a nuclear envelope (NE) protein, is also expressed in anuclear cell types to regulate membrane structure and function. We find that emerin is localized to the RBC plasma membrane and regulates the localization of other membrane proteins involved in actin branching and cytoskeletal dynamics. Additionally, we find that loss of Emd in mice results in decreased RBC corpuscular volume and hemoglobin content in both sexes, as well as a male-specific increase in RBC number and hematocrit, consistent with other male-dominated EMD phenotypes. Along with decreased RBC size, we observed a reduction in the rate of osmotic lysis in Emd KO animals, particularly males. We found that human EMD mutations also have a statistically significant association with RBC phenotypes, namely MCV. Individuals with emerin-related Emery-Dreifuss muscular dystrophy (EDMD) also demonstrate a mild yet consistent RBC phenotype according to patient CBC data. Together, these data suggest that emerin can have cell-specific localization and functions independent of its canonical repertoire in nucleated cells.

cell biology↗

bioRxiv2024

Polycomb Repressive Complex 2 promotes atherosclerotic plaque vulnerability

Key findings1. PRC2 regulates EC shear stress responses. 2. PRC2 governs Klf2/4 suppression downstream of Pcdhg. 3. High PRC2 in ASCVD-prone arterial regions suppresses Klf2/4 to promote ASCVD. 4. Athero-protective Klf2/4 induction upon PRC2 inhibition requires Notch signaling. 5. Tazemetostat, an FDA approved PRC2 inhibitor, slows ASCVD progression and improves markers of plaque stability. Atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide, is driven by endothelial cell inflammatory activation and counter-balanced by anti-inflammatory transcription factors Klf2 and Klf4 (Klf2/4). Understanding vascular endothelial inflammation to develop effective treatments is thus essential. Here, we identify, Polycomb Repressive Complex (PRC) 2, which blocks gene transcription by trimethylating histone3 Lysine27 in gene promoter/enhancers, as a potent, therapeutically targetable determinant of vascular inflammation and ASCVD progression. Bioinformatics identified PRC2 as a direct suppressor of Klf2/4 transcription. Klf2/4 transcription requires Notch signaling, which reverses PRC2 modification of Klf2/4 promoter/enhancers. PRC2 activity is elevated in human ASCVD endothelium. Treating mice with established ASCVD with tazemetostat, an FDA approved pharmacological inhibitor of PRC2, slowed plaque progression by 50% and drastically improved markers of plaque stability. This study elucidates a fundamental mechanism of vascular inflammation, thus identifying a potential method for treating ASCVD and possibly other vascular inflammatory diseases.

cell biology↗

bioRxiv2024

SUV39H1 mediated regulation of KLF4 and KDM4A coordinate smooth muscle cell phenotypic plasticity

BackgroundReversible DNA methylation contributes to the phenotypic plasticity of vascular smooth muscle cells (VSMCs). This plasticity contributes to vascular growth remodeling, but also underlies cardiovascular pathologies, including intimal hyperplasia. We investigated the role of SUV39H1, a histone methyltransferase that generates the H3K9me3 repressive epigenetic mark, in VSMC plasticity MethodsWe applied knockdown, qPCR, western blotting, chromatin immunoprecipitation (ChIP) assays, and RNA-Seq in human coronary artery SMCs (hCASMCs), and murine carotid ligation to determine the role of SUV39H1 in VSMC plasticity. ResultsExpression of SUV39H1 and the H3K9me3 mark it generates increase, whereas the cognate H3K9me3 demethylase KDM4A decreases, over time during the progression of murine intimal hyperplasia following carotid artery ligation, with marked elevation of SUV39H1 and H3K9me in the neointima. SUV39H1 knockdown induced contractile genes and contractility while decreasing migration and proliferation in hCASMCs. Transcriptomic analysis confirmed that SUV39H1 promotes SMC dedifferentiation. SUV39H1 knockdown revealed that SUV39H1 promotes KLF4 upregulation by increasing KLF4 mRNA stability. PDGF-BB induced SUV39H1 expression and SUV39H1-dependent H3K9me3 modification of contractile gene promoters in hCASMC. SUV39H1 knockdown reduced the repressive H3K9me3 and 5mC marks but increased the activating H3K27Ac mark at these promoters. SUV39H1 knockdown also increased expression of KDM4A and its binding to contractile promoters, suggesting an opposing regulatory relationship between the writer and eraser of H3K9me3. ConclusionsWe identify SUV39H1 as an epigenetic regulator that promotes VSMC dedifferentiation by stabilizing KLF4 expression and by altering chromatin state. We report SUV39H1-dependent dynamic regulation of the repressive H3K9me3 mark at contractile gene promoters, and opposing regulation of the enzymes that write (SUV39H1) and erase (KDM4A) these marks during VSMC phenotypic switching. These studies suggest that coordinate regulation of both histone and DNA methylation contribute to VSMC phenotypic plasticity. HighlightsO_LIThe histone methyl transferase SUV39H1 is differentially regulated in VSMC phenotypic switching in culture and in vascular remodeling. SUV39H1 and the H3K9me3 mark it generates increase, whereas the cognate H3K9me3 eraser KDM4A decreases, during the progression of murine intimal hyperplasia. C_LIO_LISUV39H1 promotes PDGF-induced VSMC de-differentiation, stabilizing KLF4 mRNA. SUV39H1 opposes VSMC contractility and promotes proliferation and migration. C_LIO_LIPDGF-BB induces SUV39H1-dependent H3K9me3 marks at VSMC contractile gene promoters, and SUV39H1 loss of function alters multiple marks that govern chromatin accessibility at these promoters, with opposing effects on the repressive H3K9me3 and 5mC and activating H3K27Ac marks. C_LIO_LISUV39H1 generates H3K9me3 marks that are associated with silenced heterochromatin. We note dynamic regulation of this mark at VSMC contractile gene promoters, and opposing regulation of the enzymes that write (SUV39H1) and erase (KDM4A) these marks during VSMC phenotypic switching. C_LI

cell biology↗

bioRxiv2024

Integrin-deficient T cell leukemia accumulates in the central nervous system

T-cell acute lymphoblastic leukemia (T-ALL) spreads aggressively to the central nervous system (CNS), particularly the leptomeninges. Children with T-ALL are treated with high-dose, CNS-directed chemotherapy, which can cause lasting neurotoxicity and is not always effective. Little is known about how T-ALL enters and persists within the CNS. However, normal T cell migration into the CNS has been extensively studied. Two integrins--VLA-4 and LFA-1--mediate normal T cell entry to the CNS, and VLA-4 blockade effectively treats multiple sclerosis by excluding T cells from the brain. We hypothesized that these integrins would likewise be required for T-ALL CNS entry. Unexpectedly, not only were VLA-4 and LFA-1 dispensable for T-ALL to reach the CNS, integrin-deficient T-ALL accumulated in the CNS compared to control. Mechanistically, integrin loss accelerated T-ALL proliferation in the CNS, suggesting that integrin-mediated interactions may promote quiescence in this space. Integrin blockade synergized with chemotherapy targeting proliferating cells, raising the possibility that combination therapy might be a powerful strategy.

immunology↗

bioRxiv2024

Epigenetic Remodeling in Human Coronary Artery Smooth Muscle Cell Phenotypic Switching

BackgroundSmooth muscle cell (SMC) dedifferentiation contributes to repair and remodeling, but also cardiovascular pathologies. To understand this plasticity, the epigenetic landscape in SMC phenotypic switching was profiled. MethodsGenome-wide analyses of histone modifications (ChIP-seq), chromatin architecture (ATAC-seq), and transcriptomes (RNA-seq) were performed on human coronary artery SMCs (CASMC) treated with rapamycin (contractile phenotype) and PDGF-BB (synthetic phenotype). ResultsAnalyses of differentially acetylated promoter regions identified ZEB and ZBT7A as novel enriched regulatory motifs. There were more changes in the enhancer epigenome than in promoters in CASMC phenotypic switching. Rapamycin-activated enhancers were associated with differentiation and TGF-{beta} signaling pathways and were most enriched in TEAD, SRF and SMAD motifs, whereas PDGF-induced enhancers were associated with ERK signaling and migration pathways, and were most enriched in ETV4, SOX5, and FOS motifs. GATA, TEAD, and SMCA1 motifs were enriched in CASMC enhancer open chromatin compared to other cell types. Candidate enhancers with single nucleotide polymorphisms linked to cardiovascular disease were markedly enriched in active enhancers and super enhancers and showed significant activity in reporter assays. In CASMC promoters and enhancers, common regulatory motifs were often enriched in both the differentiated and dedifferentiated phenotypes, suggesting that differential cofactor binding, as occurs with SRF at CArG elements, may be a more widespread mechanism underlying phenotypic switching. ConclusionsThese data identify novel regulatory elements engaged in SMC phenotypic switching and provide a comprehensive profile of SMC promoters, enhancers, super enhancers, and chromatin accessibility as a significant resource for studies of CASMC phenotype. Research PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIThis work identifies key regulatory elements and widespread changes in chromatin accessibility engaged in SMC phenotypic switching, including novel motifs enriched in promoters and enhancers. In CASMC promoters and enhancers, common regulatory motifs were often enriched in both the differentiated and dedifferentiated phenotypes, suggesting that differential cofactor binding, as occurs with SRF at CArG elements, may be a more widespread mechanism underlying phenotypic switching. C_LIO_LIThis work identifies distinct enhancer profiles: enhancers activated by rapamycin were associated with TGF-{beta} signaling and differentiation, while PDGF-induced enhancers were associated with ERK signaling and migration. C_LIO_LIEnhancer elements containing single nucleotide polymorphisms (SNPs) associated with cardiovascular disease from genome wide association studies (GWAS) showed notable enrichment across active enhancers and super enhancers. Select enhancers demonstrated statistically significant activity in reporter gene assays. C_LI What Question Should Be Addressed Next?O_LIThe cis regulatory elements identified in this work suggest new transcription factors that can be tested to determine whether and how they may influence SMC phenotypic modulation. C_LIO_LIThese studies could be extended to other stimuli to identify epigenomic signatures associated with CASMC transitions to other phenotypes including macrophages and chondrocytes. C_LI

genomics↗

bioRxiv2024

VEGF counteracts shear stress-determined arterial fate specification during capillary remodeling.

Postnatal vascular morphogenesis is a dynamic process that initially involves angiogenesis to form the capillary bed, followed by its partial remodeling into arteries. Vascular endothelial growth factor A (VEGF hereafter), the primary inducer of angiogenesis, is also implicated in arterial specification in developmental contexts. However, it is unclear why arterial patterning is spatiotemporally segregated from angiogenesis, while postnatal arterial specification in animal models with blocked VEGF signaling remains unstudied. Here, we report that VEGF does not induce arterial fate in the capillaries, instead serving as a physiological brake to attenuate fluid shear stress (FSS)-driven capillary-to-arterial cell fate transition. Mouse models with disrupted VEGF signaling reveal impaired angiogenesis but intact and ectopic arterialization. Mechanistically, mechanosensitive transcription factor Sox17 determines the FSS-arterial program, while VEGF suppresses Sox17 transcription activity at arterial promoters and enhancers sites. Angiogenic signaling, while essential for the initial capillary morphogenesis, inhibits arterial specification, thereby protecting the capillary bed from premature arterialization driven by flow. These findings establish a new paradigm in which precise spatiotemporal coordination of environmental stimuli orchestrates angiogenesis, arterial patterning and capillary maintenance during vascular morphogenesis.

developmental biology↗

bioRxiv2023

Microbe-derived indole tunes organ-function and links microbe metabolites to biological ageing

To investigate the underlying molecular mechanisms on how the gut microbe metabolite, indoles, regulate host organ growth and function, germ-free male mice were mono-colonized with indole-producing wildtype Escherichia coli or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli. The indole mutant E. coli recipient mice exhibited significant multiorgan decline and growth retardation combined with catabolism and energy deficiency despite increased food intake compared to control mice. In addition, indole mutant mice displayed malfunctional intestine, enlarged caecum, reduced numbers of colonic enterochromaffin cells and reduced circulating serotonin levels, resulting in reduced gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice also displayed decreased expression of Kcnj12 gene, suggesting reduced excitability of enteric neurons thus adding to intestinal dysfunctional phenotype. In conclusion, indoles are necessary to maintain adult metabolic homeostasis across multiple organs in vivo. Impairment of indole levels results in multiorgan functional decline suggesting a mechanism whereby gut microbe metabolites may regulate biological ageing and thus increase the risk for disease. Graphical summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/525337v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@182875dorg.highwire.dtl.DTLVardef@8525e9org.highwire.dtl.DTLVardef@17c24e3org.highwire.dtl.DTLVardef@159dff4_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2022

Genetic characterization of the zoonotic parasite Ancylostoma caninum in the central and eastern USA

Ancylostoma caninum is the most common nematode parasite of dogs in the United States. This study aimed to describe the molecular epidemiology of A. caninum isolates from the central and eastern states of the U.S. using the partial mitochondrial cox1 gene and to compare them with those reported globally. We isolated eggs from fecal samples of dogs and characterized each isolate based on cox1 sequences. A total of 60 samples originating from Kansas, Iowa, New York, Florida, and Massachusetts were included. 25 haplotypes were identified in the U.S. dataset with high haplotype diversity (0.904). Sequence data were compared to sequences from other world regions available in GenBank. Global haplotype analysis demonstrated 35 haplotypes with a haplotype diversity of 0.931. Phylogenetic and network analysis provide evidence for the existence of moderate geographical structuring of A. caninum haplotypes. Our results provide an updated summary of A. caninum haplotypes and data for neutral genetic markers with utility for tracking hookworm populations. Sequences have been deposited in GenBank (ON980650 - ON980674). Further studies of isolates from other regions are essential to understand the genetic diversity of this parasite.

microbiology↗

bioRxiv2022

Vagus nerve stimulation recruits the central cholinergic system to enhance perceptual learning

Perception can be refined by experience up to certain limits. It is unclear if perceptual limitations are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest the utility of peripheral nerve stimulation - specifically vagus nerve stimulation (VNS) - for altering neural activity and augmenting experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS occurring during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Using two-photon imaging, we identified changes to auditory cortical responses and activation of cortically-projecting cholinergic axons with VNS. Anatomical and optogenetic experiments indicated that VNS could enhance task performance via activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS, perhaps enabling further refinement of VNS methodology for clinical conditions.

neuroscience↗

bioRxiv2022

Bone marrow age dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to [~]70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin {beta}3 resulting in increased tumor necrosis factor [TNF]- signaling. In turn, TNF signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin {beta}3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies. Graphical abstractAge of BM-derived monocytes/macrophages determines clonality of SMC lineage in the atherosclerotic plaque. Atherogenesis is depicted in a young (a) or aged (b) host. Aged monocytes/macrophages have decreased levels of the epigenetic regulator TET2, leading to reduction of the 5-hydroxymethylcytosine (5hmC) mark on the Itgb3 promoter. The resulting low integrin {beta}3 levels in aged monocytes/macrophages induces high TNF- levels, facilitating recruitment and expansion of multiple SMC progenitors (polyclonality) in the atherosclerotic plaque and worse disease burden. In contrast, the young control is characterized by mono/oligoclonal SMC expansion in a smaller plaque. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/476756v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@12f7090org.highwire.dtl.DTLVardef@186ff92org.highwire.dtl.DTLVardef@1f4da69org.highwire.dtl.DTLVardef@2f509c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2021

Neural circuitry for maternal oxytocin release induced by infant cries

Oxytocin is a neuropeptide important for maternal physiology and childcare, including parturition and milk ejection during nursing1-8. Suckling triggers oxytocin release, but other sensory cues- specifically infant cries- can elevate oxytocin levels in new human mothers9-11 indicating that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit routing auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not pure tones, via input from the posterior intralaminar thalamus, and repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behavior in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.

neuroscience↗

bioRxiv2020

Innate sensitivity and plastic mechanisms in auditory cortex for reliable maternal behavior

Infant cries evoke powerful responses in parents1-4. To what extent are parental animals innately sensitive to neonatal vocalizations, or might instead learn about key vocal cues for appropriate parenting responses? In mice, naive virgins do not recognize the meaning of pup distress calls, but begin to retrieve pups to the nest following cohousing with a mother and litter5-8. These isolation calls can be variable, requiring co-caring virgins to generalize across features for reliable retrieval9, 10. Here, using behavioral studies combined with two-photon imaging and whole-cell recordings, we show that the onset of maternal behavior in mice results from the interaction between innate sensitivities and experience-dependent processes. We found that pup calls with inter-syllable intervals (ISIs) ranging from 75 to 375 ms elicited pup retrieval, and experienced auditory cortex generalized across these ISIs. In contrast, naive cortex was narrowly tuned to the most common or prototypical ISIs due to enhanced short-term depression of inhibitory inputs. Behavioral testing revealed that naive virgins were also more sensitive to prototypical calls than calls at other rates. Inhibitory and excitatory spiking and synaptic responses were initially mismatched in naive cortex, with untuned inhibition and overly-narrow excitation. Monitoring neuronal populations over cohousing revealed that excitatory neuronal responses broadened to represent a wide range of ISIs, while inhibitory neurons sharpened to form a perceptual boundary. Finally, we presented synthetic calls during cohousing and observed that neural and behavioral responses adjusted to match these statistics. Using inhibitory optogenetics, we found that auditory cortical activity was required to learn about specific features, whereas the oxytocinergic system was generally recruited for retrieval learning and plasticity in temporal tuning. Neuroplastic mechanisms therefore build on an innate sensitivity in the auditory cortex, enabling rapid plasticity for reliable parenting behavior.

neuroscience↗

bioRxiv2019

Flexible routing of motor control signals through neocortical projection neuron classes

The interaction of descending neocortical outputs and subcortical premotor circuits is critical for shaping the skilled movements. Two broad classes of motor cortical output projection neurons provide input to many subcortical motor areas: pyramidal tract neurons (PT), which project throughout the neuraxis; and intratelencephalic neurons (IT), which project within cortex and subcortical striatum. It is unclear whether these classes are functionally in series or whether separable components of descending motor control signals are distributed across these distinct classes of projection neurons. Here we combine large-scale neural recordings across all layers of motor cortex with cell-type specific perturbations to study cortically-dependent mouse motor behaviors: kinematically-variable manipulation of a joystick and a kinematically-precise reach-to-grasp. We find that striatum-projecting IT neuron activity preferentially represents amplitude whereas pons-projecting PT neurons preferentially represent the variable direction of forelimb movements. Thus, separable components of descending motor cortical commands are distributed across motor cortical projection cell classes. One-sentence summarySeparable components of cortical motor commands are distributed across distinct glutamatergic projection neuron cell-types.

neuroscience↗

bioRxiv2018

TCF7L2 Regulation of GATA6-dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia

Genetic variations in Wnt-coreceptor LRP6 and Wnt-regulated transcription factor TCF7L2 have been among the strongest genetic signals for type2 diabetes (T2DM) and coronary artery disease (CAD). Mice with a CAD-linked LRP6 mutation exhibit obstructive coronary artery disease characterized by reduced TCF7L2 expression and dedifferentiation of vascular smooth muscle cell (VSMC). While TCF7L2 maintains stemness and promotes proliferation in embryonic tissues and adult stem cells, its role and mechanisms of action in VSMC differentiation is not understood. Using multiple mouse models, we demonstrate here that TCF7L2 promotes differentiation and inhibits proliferation of VSMCs. TCF7L2 accomplishes these effects by stabilization of GATA6 and upregulation of SM-MHC and cell cycle inhibitors. Accordingly, TCF7L2 haploinsufficient mice exhibited increased susceptibility to, while mice overexpressing TCF7L2 were protected against injury-induced intimal hyperplasia compared to wildtype littermates. Consequently, the overexpression of TCF7L2 in LRP6 mutant mice rescued the injury induced intimal hyperplasia. These novel findings imply cell type-specific functional role of TCF7L2 and provide critical insight into poorly understood mechanisms underlying pathogenesis of intimal hyperplasia.

molecular biology↗

bioRxiv2016

Behavioral evidence for feedback gain control by the inhibitory microcircuit of the substantia nigra

We recently demonstrated that the collaterals of substantia nigra (SN) projection neurons can implement divisive feedback inhibition, or gain control (Brown et al., 2014). While in vivo recordings were consistent with divisive feedback inhibition, a causal test was lacking. A gain control model of the nigral microcircuit implies behavioral effects of disrupting intranigral inhibition that are distinct from previous functional models. To test the model predictions experimentally, we develop a chemogenetic approach that can selectively suppress synaptic release within the substantial nigra without affecting the propagation of activity to extranigral targets. We observe behavioral consequences of suppressing intranigral inhibition that are uniquely consistent with a gain control model. Our data further suggest that if endogenous metabotropic signaling can modulate intranigral synapses, this would provide a circuit mechanism for an exploitation/exploration trade-off in which the timing and variability of goal-directed movements are controlled independently of changes in action.

neuroscience↗