Seth R. Batten

Biogenic amines are fundamental for physiological homeostasis and behavioral control in both vertebrates and invertebrates. Monoamine neurotransmitters released in target brain regions conjointly regulate adaptive learning and plasticity. However, our understanding of these multianalyte mechanisms remains nascent, in part due to limitations in measurement technology. Here, during associative conditioning in honey bees, we concurrently tracked subsecond fluctuations in octopamine, tyramine, dopamine, and serotonin in the antennal lobe, where plasticity influences odorant representations. By repeatedly pairing an odorant with subsequent sucrose delivery, we observed individual differences in the conditioned response to odor, which occurred after a variable number of pairings (learners) or not at all (non-learners). The distinction between learners and non-learners was reflected in neurotransmitter responses across experimental conditions. The speed of learning, the number of pairings prior to a proboscis extension reflex, could be predicted from monoamine opponent signaling (octopamine-tyramine), from both the first presentation of the odorant alone, prior to any pairing with sucrose, and the first conditioned response to the odorant, coming after a number of sucrose pairings. These results suggest that monoamine signaling phenotypes may relate directly to the now widely reported socially relevant genetic differences in honey bee learning.

Recent advances in deep brain stimulation (DBS) of the subcallosal cingulate (SCC) show promise in mitigating the symptoms of treatment-resistant depression (TRD) in humans ^1–3 . Monoamines, such as dopamine and serotonin, mediate the effects of pharmacological treatments of depression. However, their roles in recovery following DBS remain elusive, largely due to technical limitations of measuring these neurotransmitters in the living human brain. Here, by leveraging machine learning-enhanced electrochemistry ^4–7 , we show that dopamine and serotonin signaling following DBS to the SCC predicted later depressive symptom relief in humans with TRD. We found that both dopamine and serotonin levels increased following subtherapeutic intraoperative SCC stimulation, with each neurotransmitter showing selective responses to distinct decision-making tasks. Furthermore, acute dopamine increases predicted later mood improvements during a social decision-making task, while serotonin enhancement predicted faster responses during a non-social learning task longitudinally. Critically, changes in dopamine and serotonin levels during the social decision-making task jointly predicted depressive symptom remission at 6-month follow-up. These findings illustrate the contribution of both dopamine and serotonin signaling in predicting behavioral improvement and depressive symptom remission in humans with TRD. Such neurochemical plasticity may serve as potential mechanistic biomarkers for SCC DBS mechanism and TRD treatment response. Significance statement: Dopamine and serotonin levels increased following acute DBS to the SCC in humans. Acute dopamine and serotonin changes predicted later mood and response speed changes. Sustained TRD recovery was predicted by acute increases in both dopamine and serotonin estimates.

Dynamic changes in dopamine, noradrenaline, and serotonin release are believed to causally contribute to the neural computations that support reward-based decision making. Accordingly, changes in signaling by these systems are hypothesized to underwrite multiple cognitive and behavioral symptoms observed in many neurological disorders. Here, we characterize the release of these neurotransmitters measured concurrently in the caudate of patients with Parkinson's disease or essential tremor undergoing deep brain stimulation surgery as they played a social exchange game. We show that violations in the expected value of monetary offers are encoded by opponent patterns of dopamine and serotonin release in essential tremor, but not Parkinson's disease, patients. We also demonstrate that these changes in serotonin signaling comprise a neurochemical boundary that subsegments these two neuromotor diseases. Our combined results point to a neural signature of altered reward processing that can be used to understand the signaling deficiencies that underwrite these diseases.

Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson’s disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value—akin to reward prediction errors—whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia’s main output structures reflect distinct social context and value signals.

The attribution of incentive salience to reward‐predictive stimuli has been shown to be associated with substance abuse‐like behavior such as increased drug taking. Evidence suggests that glutamate neurotransmission and sequential N‐methyl‐D‐aspartate (NMDA) activation are involved in the attribution of incentive salience. Here, we further explore the role of second‐by‐second glutamate neurotransmission in the attribution of incentive salience to reward‐predictive stimuli by measuring sign‐tracking behavior during a Pavlovian conditioned approach procedure using ceramic‐based microelectrode arrays configured for sensitive measures of extracellular glutamate in awake behaving Sprague‐Dawley rats. Specifically, we show that there is an increase in extracellular glutamate levels in the prelimbic cortex (PrL) and the nucleus accumbens core (NAcC) during sign‐tracking behavior to a food‐predictive conditioned stimulus (CS+) compared to the presentation of a non‐predictive conditioned stimulus (CS−). Furthermore, the results indicate greater increases in extracellular glutamate levels in the PrL compared to NAcC in response to the CS+, including differences in glutamate release and signal decay. Taken together, the present research suggests that there is differential glutamate signaling in the NAcC and PrL during sign‐tracking behavior to a food‐predictive CS+. image

Introduction: In kindling, repeated electrical stimulation of certain brain areas causes progressive and permanent intensification of epileptiform activity resulting in generalized seizures. We focused on the role(s) of glutamate and a negative regulator of glutamate release, STXBP5/tomosyn‐1, in kindling.Methods: Stimulating electrodes were implanted in the amygdala and progression to two successive Racine stage 5 seizures was measured in wild‐type and STXBP5/tomosyn‐1^−/− (Tom^−/−) animals. Glutamate release measurements were performed in distinct brain regions using a glutamate‐selective microelectrode array (MEA).Results: Naïve Tom^−/− mice had significant increases in KCl‐evoked glutamate release compared to naïve wild type as measured by MEA of presynaptic release in the hippocampal dentate gyrus (DG). Kindling progression was considerably accelerated in Tom^−/− mice, requiring fewer stimuli to reach a fully kindled state. Following full kindling, MEA measurements of both kindled Tom^+/+ and Tom^−/− mice showed significant increases in KCl‐evoked and spontaneous glutamate release in the DG, indicating a correlation with the fully kindled state independent of genotype. Resting glutamate levels in all hippocampal subregions were significantly lower in the kindled Tom^−/− mice, suggesting possible changes in basal control of glutamate circuitry in the kindled Tom^−/− mice.Conclusions: Our studies demonstrate that increased glutamate release in the hippocampal DG correlates with acceleration of the kindling process. Although STXBP5/tomosyn‐1 loss increased evoked glutamate release in naïve animals contributing to their prokindling phenotype, the kindling process can override any attenuating effect of STXBP5/tomosyn‐1. Loss of this “braking” effect of STXBP5/tomosyn‐1 on kindling progression may set in motion an alternative but ultimately equally ineffective compensatory response, detected here as reduced basal glutamate release.

In animal models of substance‐use disorder, individuals that repeatedly self‐administer drugs of abuse have long‐lasting neuronal adaptations that do not occur ostensibly in control animals only exposed to natural reinforcers (e.g. food). Because any treatment for substance‐use disorder will be given to individuals with drug‐taking histories, adequate dissociation of the specific neurobehavioral mechanisms underlying drug reinforcement, natural reinforcement and their associated cue effects requires an experimental model that exposes individuals to both reinforcer conditions, along with their associated stimuli. Furthermore, contingent stimuli that reinforce drug seeking through second‐order relationships may produce reinstatement of drug seeking through different neurobehavioral means than non‐contingent exposure to stimuli that signal the availability of a drug reinforcer, effectively producing different modes of stimulus‐induced reinstatement. Toward experimental isolation of the relationships mentioned, herein, we used a within‐session multiple schedule of reinforcement containing both discriminative (S^D) and conditioned (CS) stimuli to study stimulus control of drug‐taking and food‐taking behavior, along with how these functionally distinct cues may differentially reinstate drug‐seeking and food‐seeking behavior within a single animal. We demonstrate specific stimulus control over drug and food taking; furthermore, we demonstrate that the same stimulus (i.e. cue light) operating as an S^D or CS produced differential reinstatement of drug‐taking and food‐taking behavior. The results suggest that contingent CSs and non‐contingent S^Ds produce reinstatement through different neurobehavioral processes and, within‐session multiple schedules, can be used to study different modes of specific stimulus control over drug and food seeking in a single animal with both drug‐taking and food‐taking history.