Like ventral tegmental area (VTA) dopamine (DA) neurons, VTA glutamate neuron activity can support positive reinforcement. However, a subset of VTA neurons co-release DA and glutamate, and DA release ...might be responsible for behavioral reinforcement induced by VTA glutamate neuron activity. To test this, we used optogenetics to stimulate VTA glutamate neurons in which tyrosine hydroxylase (TH), and thus DA biosynthesis, was conditionally ablated using either floxed Th mice or viral-based CRISPR/Cas9. Both approaches led to loss of TH expression in VTA glutamate neurons and loss of DA release from their distal terminals in nucleus accumbens (NAc). Despite loss of the DA signal, optogenetic activation of VTA glutamate cell bodies or axon terminals in NAc was sufficient to support reinforcement. These results suggest that glutamate release from VTA is sufficient to promote reinforcement independent of concomitant DA co-release, establishing a non-DA mechanism by which VTA activity can support reward-seeking behaviors.
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•Activation of VTA glutamate neurons can reinforce behavior•Activation of VTA glutamate neurons also leads to dopamine (DA) release•We generated two distinct models to abolish this coincident DA signal•VTA glutamate neuron activity can serve as a reinforcer independent from DA
Activation of VTA glutamate neurons leads to dopamine co-release in nucleus accumbens. Zell et al. genetically block this dopamine signal to show that VTA glutamate projections to nucleus accumbens can reinforce behaviors independently. These findings establish a parallel dopamine-independent mesolimbic pathway capable of supporting positive reinforcement.
A vast array of animal behavior—from locomotion to human speech—is thought to consist of different hierarchical levels, but its neural implementation remains poorly understood. In this issue of ...Neuron, Kaplan et al. (2020) identify neuronal circuit dynamics responsible for multiple levels and timescales of hierarchical locomotion control in Caenorhabditis elegans.
A vast array of animal behavior—from locomotion to human speech—is thought to consist of different hierarchical levels, but its neural implementation remains poorly understood. In this issue of Neuron, Kaplan et al. (2020) identify neuronal circuit dynamics responsible for multiple levels and timescales of hierarchical locomotion control in Caenorhabditis elegans.
Exposure to stress has profound, but complex, actions on motivated behavior and decision-making. These effects are central to core symptoms of a number of psychiatric disorders that are precipitated ...or augmented by stress, such as depressive disorders and substance use disorders. Studying the neural substrates of stress's effects on motivation has revealed that stress affects multiple targets on circuits throughout the brain using diverse molecular signaling processes. Moreover, stress does not have unitary effects on motivated behavior, but differences in the intensity, duration, intermittency, controllability and nature of the stressor produce qualitatively and quantitatively different behavioral endpoints. Unsurprisingly, the results of neuroscientific investigations into stress and motivation often open more questions than they resolve. Here we discuss contemporary results pertaining to the neural mechanisms by which stress alters motivation, identify points of contention and highlight integrative areas for continuing research into these multifaceted complexities.
The striatum contains neurochemically defined compartments termed patches and matrix. Previous studies suggest patches preferentially receive limbic inputs and project to dopamine neurons in ...substantia nigra pars compacta (SNc), whereas matrix neurons receive sensorimotor inputs and do not innervate SNc. Using BAC-Cre transgenic mice with viral tracing techniques, we mapped brain-wide differences in the input-output organization of the patch/matrix. Findings reveal a displaced population of striatal patch neurons termed “exo-patch,” which reside in matrix zones but have neurochemistry, connectivity, and electrophysiological characteristics resembling patch neurons. Contrary to previous studies, results show patch/exo-patch and matrix neurons receive both limbic and sensorimotor information. A novel inhibitory projection from bed nucleus of the stria terminalis to patch/exo-patch neurons was revealed. Projections to SNc were found to originate from patch/exo-patch and matrix neurons. These findings redefine patch/matrix beyond traditional neurochemical topography and reveal new principles about their input-output connectivity, providing a foundation for future functional studies.
•Redefines striatal patch compartment to include “exo-patch” SPNs in the matrix zone•Novel GABAergic projections from the BNST targets striatal patch/exo-patch SPNs•Both striatal patch and matrix receive limbic and sensorimotor information•Corticostriatal projections to patch and matrix originate from equivalent layers
Using BAC-Cre transgenic mice with Cre-dependent viral tracing, electrophysiology, and optogenetics, Smith, Klug, Ross et al. reveal new striatal circuitry and redefine the input-output organization of striatal patch and matrix compartments.
Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress ...promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.
The ventral pallidum (VP) contains GABA and glutamate neurons projecting to ventral tegmental area (VTA) whose stimulation drives approach and avoidance, respectively. Yet little is known about the ...mechanisms by which VP cell types shape VTA activity and drive behavior. Here, we found that both VP GABA and glutamate neurons were activated during approach to reward or by delivery of an aversive stimulus. Stimulation of VP GABA neurons inhibited VTA GABA, but activated dopamine and glutamate neurons. Remarkably, stimulation-evoked activation was behavior-contingent such that VTA recruitment was inhibited when evoked by the subject's own action. Conversely, VP glutamate neurons activated VTA GABA, as well as dopamine and glutamate neurons, despite driving aversion. However, VP glutamate neurons evoked dopamine in aversion-associated ventromedial nucleus accumbens (NAc), but reduced dopamine release in reward-associated dorsomedial NAc. These findings show how heterogeneous VP projections to VTA can be engaged to shape approach and avoidance behaviors.
Rats emit ultrasonic vocalizations (USVs) that are thought to serve as situation-dependent affective signals and accomplish important communicative functions. In appetitive situations, rats produce ...50 kHz USVs, whereas 22 kHz USVs occur in aversive situations. Reception of 50 kHz USVs induces social approach behavior, while 22 kHz USVs lead to freezing behavior. These opposite behavioral responses are paralleled by distinct brain activation patterns, with 50 kHz USVs, but not 22 kHz USVs, activating neurons in the nucleus accumbens (NAcc). The NAcc mediates appetitive behavior and is critically modulated by dopaminergic afferents that are known to encode the value of reward. Therefore, we hypothesized that 50 kHz USVs, but not 22 kHz USVs, elicit NAcc dopamine release. While recording dopamine signaling with fast-scan cyclic voltammetry, freely moving rats were exposed to playback of four acoustic stimuli via an ultrasonic speaker in random order: (1) 50 kHz USVs, (2) 22 kHz USVs, (3) time- and amplitude-matched white noise, and (4) background noise. Only presentation of 50 kHz USVs induced phasic dopamine release and elicited approach behavior toward the speaker. Both of these effects, neurochemical and behavioral, were most pronounced during initial playback, but then declined rapidly with subsequent presentations, indicating a close temporal relationship between the two measures. Moreover, the magnitudes of these effects during initial playback were significantly correlated. Collectively, our findings show that NAcc dopamine release encodes pro-social 50 kHz USVs, but not alarming 22 kHz USVs. Thus, our results support the hypothesis that these call types are processed in distinct neuroanatomical regions and establish a functional link between pro-social communicative signals and reward-related neurotransmission.
Highlights ► We apply a multiple systems framework to Pavlovian valuation. ► Recent evidence supports a selective role for dopamine in model-free Pavlovian valuation. ► Recent evidence supports a ...preferential role for the orbitofrontal cortex in model-based Pavlovian valuation. ► We discuss the implications of interaction between valuation systems for learning and decision making.
Ventral tegmental area (VTA) projections to the nucleus accumbens (NAc) drive reward-related motivation. Although dopamine neurons are predominant, a substantial glutamatergic projection is also ...present, and a subset of these co-release both dopamine and glutamate. Optogenetic stimulation of VTA glutamate neurons not only supports self-stimulation but can also induce avoidance behavior, even in the same assay. Here, we parsed the selective contribution of glutamate or dopamine co-release from VTA glutamate neurons to reinforcement and avoidance. We expressed channelrhodopsin-2 (ChR2) in mouse VTA glutamate neurons in combination with CRISPR-Cas9 to disrupt either the gene encoding vesicular glutamate transporter 2 (VGLUT2) or tyrosine hydroxylase (Th). Selective disruption of VGLUT2 abolished optogenetic self-stimulation but left real-time place avoidance intact, whereas CRISPR-Cas9 deletion of Th preserved self-stimulation but abolished place avoidance. Our results demonstrate that glutamate release from VTA glutamate neurons is positively reinforcing but that dopamine release from VTA glutamate neurons can induce avoidance behavior.
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•VTA glutamate/dopamine neurons are activated by aversive and appetitive stimuli•Activation of VTA glutamate neurons is reinforcing and aversive•Glutamate released from VTA glutamate neurons is reinforcing•Dopamine co-released from VTA glutamate neurons is aversive
VTA glutamate neurons co-release glutamate and dopamine in the nucleus accumbens, and their activation is associated with both positive reinforcement and aversion. Warlow et al. demonstrate that disrupting glutamate release from VTA glutamate neurons selectively abolishes positive reinforcement, whereas disrupting their ability to co-release dopamine selectively abolishes place aversion.
Background Generalized social phobia (GSP) and generalized anxiety disorder (GAD) are both associated with emotion dysregulation. Research implicates dorsal anterior cingulate cortex in both explicit ...emotion regulation (EER) and top-down attentional control (TAC). Although studies have examined these processes in GSP or GAD, no work compares findings across the two disorders or examines functioning in cases comorbid for both disorders (GSP/GAD). Here we compare the neural correlates of EER and TAC in GSP, GAD, and GSP/GAD. Methods Medication-free adults with GSP (EER n = 19; TAC n = 18), GAD (EER n = 17; TAC n = 17), GSP/GAD (EER n = 17; TAC n = 15), and no psychopathology (EER n = 18; TAC n = 18) participated. During EER, individuals alternatively viewed and upregulated and downregulated responses to emotional pictures. During TAC, they performed an emotional Stroop task. Results For both tasks, significant group × condition interactions emerged in dorsal anterior cingulate cortex and parietal cortices. Healthy adults showed significantly increased recruitment during emotion regulation, relative to emotion-picture viewing. GAD, GSP, and GSP/GAD subjects showed no such increases, with all groups differing from healthy adults but not from each other. Evidence of emotion-related disorder-specificity emerged in medial prefrontal cortex and amygdala. This disorder-specific responding varied as a function of emotion content but not emotion-regulatory demands. Conclusions GSP and GAD both involve reduced capacity for engaging emotion-regulation brain networks, whether explicitly or via TAC. A reduced ability to recruit regions implicated in top-down attention might represent a general risk factor for anxiety disorders.
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