Spatiotemporal Control of Noradrenaline-Dependent Synaptic Transmission in Mouse Dorsal Raphe Serotonin Neurons.

Activity of dorsal raphe neurons is controlled by noradrenaline afferents. In this brain region, noradrenaline activates Gαq-coupled α1-adrenergic receptors (α1-AR), causing action potential (AP) firing and serotonin release. In vitro, electrical stimulation elicits vesicular noradrenaline release and subsequent activation of α1-AR to produce an EPSC (α1-AR-EPSC). The duration of the α1-AR-EPSC (∼27 s) is much longer than that of most other synaptic currents, but the factors that govern the spatiotemporal dynamics of α1-AR are poorly understood. Using an acute brain slice preparation from adult male and female mice and electrophysiological recordings from dorsal raphe neurons, we found that the time course of the α1-AR-EPSC was slow, but highly consistent within individual serotonin neurons. The amount of noradrenaline released influenced the amplitude of the α1-AR-EPSC without altering the time constant of decay suggesting that once released, extracellular noradrenaline was cleared efficiently. Reuptake of noradrenaline via noradrenaline transporters was a primary means of terminating the α1-AR-EPSC, with little evidence for extrasynaptic diffusion of noradrenaline unless transporter-dependent reuptake was impaired. Taken together, the results demonstrate that despite slow intrinsic signaling kinetics, noradrenaline-dependent synaptic transmission in the dorsal raphe is temporally and spatially controlled and noradrenaline transporters are critical regulators of serotonin neuron excitability. Given the functionally distinct types of neurons intermingled in the dorsal raphe nucleus and the unique roles of these neural circuits in physiological responses, transporters may preserve independence of each synapse to encode a long-lasting but discrete signal.SIGNIFICANCE STATEMENT The dorsal raphe nucleus is the predominant source of serotonin in the brain and is controlled by another monoamine, noradrenaline. In this brain region, noradrenaline activates G-protein-coupled α1-adrenergic receptors (α1-AR) causing action potential (AP) firing and serotonin release. Despite high interest in pharmacotherapies to enhance serotonin signaling, the factors that govern noradrenaline α1-AR signaling have received little attention. Here, we show using mouse brain slices that the time course of α1-AR signaling is slow, persisting for tens of seconds. Despite slow intrinsic signaling kinetics, noradrenaline-dependent synaptic transmission in the dorsal raphe is controlled temporally and spatially by efficient noradrenaline transporter-dependent clearance of extracellular noradrenaline. Thus, noradrenaline transporters are critical regulators of serotonin neuron excitability.

Running from fear: Exercise modulation of fear extinction.

Extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear tends to resurface even after successful extinction. Identification of novel strategies to enhance fear extinction and reduce fear relapse is of paramount importance to mental health. Exercise can enhance cognitive function, but it is not yet well understood whether exercise can be an effective augmentation strategy for fear extinction. In the current review, we present the current state of knowledge on the effects of exercise on fear extinction. Effects of exercise duration, explanations for conflicting results, and potential mechanisms, focusing on a hypothesized role for dopamine, are all discussed. We also provide new data suggesting that the timing in which acute exercise occurs relative to fear extinction, is a crucial variable in determining whether exercise can enhance fear extinction. Clinical implications and ideas to guide future research endeavors in this area are provided.

LC-derived excitatory synaptic transmission to dorsal raphe serotonin neurons is inhibited by activation of alpha2-adrenergic receptors.

In the central nervous system, noradrenaline transmission controls the degree to which we are awake, alert, and attentive. Aberrant noradrenaline transmission is associated with pathological forms of hyper- and hypo-arousal that present in numerous neuropsychiatric disorders often associated with dysfunction in serotonin transmission. In vivo, noradrenaline regulates the release of serotonin because noradrenergic input drives the serotonin neurons to fire action potentials via activation of excitatory α1-adrenergic receptors (α1-AR). Despite the critical influence of noradrenaline on the activity of dorsal raphe serotonin neurons, the source of noradrenergic afferents has not been resolved and the presynaptic mechanisms that regulate noradrenaline-dependent synaptic transmission have not been described. Using an acute brain slice preparation from male and female mice and electrophysiological recordings from dorsal raphe serotonin neurons, we found that selective optogenetic activation of locus coeruleus terminals in the dorsal raphe was sufficient to produce an α1-AR-mediated excitatory postsynaptic current (α1-AR-EPSC). Activation of inhibitory α2-adrenergic receptors (α2-AR) with UK-14,304 eliminated the α1-AR-EPSC via presynaptic inhibition of noradrenaline release, likely via inhibition of voltage-gated calcium channels. In a subset of serotonin neurons, activation of postsynaptic α2-AR produced an outward current through activation of GIRK potassium conductance. Further, in vivo activation of α2-AR by systemic administration of clonidine reduced the expression of c-fos in the dorsal raphe serotonin neurons, indicating reduced neural activity. Thus, α2-AR are critical regulators of serotonin neuron excitability.

Nucleus Accumbens Local Circuit for Cue-Dependent Aversive Learning.

Response to threatening environmental stimuli requires detection and encoding of important environmental features that dictate threat. Aversive events are highly salient which promotes associative learning about stimuli that signal this threat. The nucleus accumbens is uniquely positioned to process this salient, aversive information and promote motivated output, through plasticity on the major projection neurons in the brain area. We uncovered a nucleus accumbens core local circuit whereby excitatory plasticity facilitates learning and recall of discrete aversive cues. We demonstrate that putative nucleus accumbens substance P release and long-term excitatory plasticity on dopamine 2 receptor expressing projection neurons is required for cue-dependent fear learning. Additionally, we found fear learning and recall were dependent on distinct projection-neuron subtypes. Our work demonstrates a critical role for Nucleus Accumbens substance P in cue-dependent aversive learning.

Nucleus accumbens local circuit for cue-dependent aversive learning.

Response to threatening environmental stimuli requires detection and encoding of important environmental features that dictate threat. Aversive events are highly salient, which promotes associative learning about stimuli that signal this threat. The nucleus accumbens is uniquely positioned to process this salient, aversive information and promote motivated output, through plasticity on the major projection neurons in the brain area. We describe a nucleus accumbens core local circuit whereby excitatory plasticity facilitates learning and recall of discrete aversive cues. We demonstrate that putative nucleus accumbens substance P release and long-term excitatory plasticity on dopamine 2 receptor-expressing projection neurons are required for cue-dependent fear learning. Additionally, we find that fear learning and recall is dependent on distinct projection neuron subtypes. Our work demonstrates a critical role for nucleus accumbens substance P in cue-dependent aversive learning.

The Structured Mind at Rest: Low-Frequency Oscillations Reflect Interactive Dynamics Between Spontaneous Brain Activity and a Common Architecture for Task Control.

The Common Model of Cognition (CMC) has been proposed as a high level framework through which functional neuroimaging data can be predicted and interpreted. Previous work has found the CMC is capable of predicting brain activity across a variety of tasks, but it has not been tested on resting state data. This paper adapts a previously used method for comparing theoretical models of brain structure, Dynamic Causal Modeling, for the task-free environment of resting state, and compares the CMC against six alternate architectural frameworks while also separately modeling spontaneous low-frequency oscillations. For a large sample of subjects from the Human Connectome Project, the CMC provides the best account of resting state brain activity, suggesting the presence of a general purpose structure of connections in the brain that drives activity when at rest and when performing directed task behavior. At the same time, spontaneous brain activity was found to be present and significant across all frequencies and in all regions. Together, these results suggest that, at rest, spontaneous low-frequency oscillations interact with the general cognitive architecture for task-based activity. The possible functional implications of these findings are discussed.

Inferring a Cognitive Architecture from Multitask Neuroimaging Data: A Data-Driven Test of the Common Model of Cognition Using Granger Causality.

Cognitive architectures (i.e., theorized blueprints on the structure of the mind) can be used to make predictions about the effect of multiregion brain activity on the systems level. Recent work has connected one high-level cognitive architecture, known as the "Common Model of Cognition," to task-based functional MRI data with great success. That approach, however, was limited in that it was intrinsically top-down, and could thus only be compared with alternate architectures that the experimenter could contrive. In this paper, we propose a bottom-up method to infer a cognitive architecture directly from brain imaging data itself, overcoming this limitation. Specifically, Granger causality modeling was applied to the same task-based fMRI data to infer a network of causal connections between brain regions based on their functional connectivity. The resulting network shares many connections with those proposed by the Common Model of Cognition but also suggests important additions likely related to the role of episodic memory. This combined top-down and bottom-up modeling approach can be used to help formalize the computational instantiation of cognitive architectures and further refine a comprehensive theory of cognition.

Delta glutamate receptor conductance drives excitation of mouse dorsal raphe neurons.

The dorsal raphe nucleus is the predominant source of central serotonin, where neuronal activity regulates complex emotional behaviors. Action potential firing of serotonin dorsal raphe neurons is driven via α1-adrenergic receptors (α1-AR) activation. Despite this crucial role, the ion channels responsible for α1-AR-mediated depolarization are unknown. Here, we show in mouse brain slices that α1-AR-mediated excitatory synaptic transmission is mediated by the ionotropic glutamate receptor homolog cation channel, delta glutamate receptor 1 (GluD1). GluD1R-channels are constitutively active under basal conditions carrying tonic inward current and synaptic activation of α1-ARs augments tonic GluD1R-channel current. Further, loss of dorsal raphe GluD1R-channels produces an anxiogenic phenotype. Thus, GluD1R-channels are responsible for α1-AR-dependent induction of persistent pacemaker-type firing of dorsal raphe neurons and regulate dorsal raphe-related behavior. Given the widespread distribution of these channels, ion channel function of GluD1R as a regulator of neuronal excitability is proposed to be widespread in the nervous system.

Serotonin is a chemical that allows cells to communicate in the nervous system of many animals. It is also particularly important in the treatment of mental health disorders: a large number of antidepressants work by preventing nerve cells from clearing away serotonin, therefore increasing the overall level of the molecule in the brain. Yet, exactly how serotonin is released remains unclear. When a serotonin-producing cell is activated, a series of biochemical processes lead to the creation of an electric current that, ultimately, is required for the cell to release serotonin. This mechanism starts when the α1-adrenergic receptor, a protein at the surface of the cell, detects noradrenaline molecules. However, on its own, the α1-adrenergic receptor is unable to create an electric current: this requires ion channels, another type of protein which can let charged particles in and out of the cell. Here, Gantz et al. set out to determine the identity of the ion channel that allows noradrenaline signals to generate electrical activity in cells which can release serotonin. Electrical and chemical manipulation of mouse brain slices revealed that an ion channel called delta-glutamate 1 was active in serotonin-producing cells exposed to noradrenaline. In fact, applying toxins that specifically blocked the activity of this channel also prevented the cells from responding electrically to noradrenaline. Further experiments used mice whose serotonin-producing cells were genetically modified to turn off delta-glutamate 1. In turn, these animals showed anxiety-like behaviors, which could be consistent with a drop in serotonin levels. This is in line with previous human studies showing that patients with depression and other mental health conditions have mutations in the gene for delta-glutamate 1. Taken together, these results give an insight into the electrical activity of serotonin-producing cells. Further work is now required to examine how changes in the gene that codes for delta-glutamate 1 ultimately affect the release of serotonin. This could potentially help to understand if certain individuals may not be able to properly produce this chemical. As many antidepressants work by retaining serotonin that is already present in the brain, this knowledge could ultimately help patients who do not currently respond to treatment.

3,4-methylenedioxymethamphetamine (MDMA) impairs the extinction and reconsolidation of fear memory in rats.

Clinical trials have demonstrated that 3,4-methylenedioxymethamphetamine (MDMA) paired with psychotherapy is more effective at reducing symptoms of post-traumatic stress disorder (PTSD) than psychotherapy or pharmacotherapy, alone or in combination. The processes through which MDMA acts to enhance psychotherapy are not well understood. Given that fear memories contribute to PTSD symptomology, MDMA could augment psychotherapy by targeting fear memories. The current studies investigated the effects of a single administration of MDMA on extinction and reconsolidation of cued and contextual fear memory in adult, male Long-Evans rats. Rats were exposed to contextual or auditory fear conditioning followed by systemic administration of saline or varying doses of MDMA (between 1 and 10 mg/kg) either 30 min before fear extinction training or immediately after brief fear memory retrieval (i.e. during the reconsolidation phase). MDMA administered prior to fear extinction training failed to enhance fear extinction memory, and in fact impaired drug-free cued fear extinction recall without impacting later fear relapse. MDMA administered during the reconsolidation phase, but not outside of the reconsolidation phase, produced a delayed and persistent reduction in conditioned fear. These findings are consistent with a general memory-disrupting effect of MDMA and suggest that MDMA could augment psychotherapy by modifying fear memories during reconsolidation without necessarily enhancing their extinction.

Activation of Nigrostriatal Dopamine Neurons during Fear Extinction Prevents the Renewal of Fear.

Manipulations that increase dopamine (DA) signaling can enhance fear extinction, but the circuits involved remain unknown. DA neurons originating in the substantia nigra (SN) projecting to the dorsal striatum (DS) are traditionally viewed in the context of motor behavior, but growing data implicate this nigrostriatal circuit in emotion. Here we investigated the role of nigrostriatal DA in fear extinction. Activation of SN DA neurons with designer Gq-coupled receptors exclusively activated by designer drugs (Gq-DREADD) during fear extinction had no effect on fear extinction acquisition, but enhanced fear extinction memory and blocked the renewal of fear in a novel context; a pattern of data paralleled by cFos expression in the central amygdala. D1 receptors in the DS are a likely target mediating the effects of SN DA activation. D1-expressing neurons in the medial DS (DMS) were recruited during fear extinction, and Gq-DREADD-induced DA potentiated activity of D1-expressing neurons in both the DMS and the lateral DS (DLS). Pharmacological activation of D1 receptors in the DS did not impact fear extinction acquisition or memory, but blocked fear renewal in a novel context. These data suggest that activation of SN DA neurons and DS D1 receptors during fear extinction render fear extinction memory resistant to the disrupting effects of changes in contextual contingencies, perhaps by recruiting habitual learning strategies involving the DLS. Nigrostriatal DA thus represents a novel target to enhance long-term efficacy of extinction-based therapies for anxiety and trauma-related disorders.

Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior.

Exercise can enhance learning and memory and produce resistance against stress-related psychiatric disorders such as depression and anxiety. In rats, these beneficial effects of exercise occur regardless of exercise controllability: both voluntary and forced wheel running produce stress-protective effects. The mechanisms underlying these beneficial effects of exercise remain unknown. The mammalian target of rapamycin (mTOR) is a translation regulator important for cell growth, proliferation, and survival. mTOR has been implicated in enhancing learning and memory as well as antidepressant effects. Moreover, mTOR is sensitive to exercise signals such as metabolic factors. The effects of exercise on mTOR signaling, however, remain unknown. The goal of the present study was to test the hypothesis that exercise, regardless of controllability, increases levels of phosphorylated mTOR (p-mTOR) in brain regions important for learning and emotional behavior. Rats were exposed to 6 weeks of either sedentary (locked wheel), voluntary, or forced wheel running conditions. At 6 weeks, rats were sacrificed during peak running and levels of p-mTOR were measured using immunohistochemistry. Overall, both voluntary and forced exercise increased p-mTOR-positive neurons in the medial prefrontal cortex, striatum, hippocampus, hypothalamus, and amygdala compared to locked wheel controls. Exercise, regardless of controllability, also increased numbers of p-mTOR-positive glia in the striatum, hippocampus, and amygdala. For both neurons and glia, the largest increase in p-mTOR positive cells was observed after voluntary running, with forced exercise causing a more modest increase. Interestingly, voluntary exercise preferentially increased p-mTOR in astrocytes (GFAP+), while forced running increased p-mTOR in microglia (CD11+) in the inferior dentate gyrus. Results suggest that mTOR signaling is sensitive to exercise, but subtle differences exist depending on exercise controllability. Increases in mTOR signaling could contribute to the beneficial effects of exercise on cognitive function and mental health.