Lack of M4 muscarinic receptors in the striatum, thalamus and intergeniculate leaflet alters the biological rhythm of locomotor activity in mice.

The deletion of M4 muscarinic receptors (MRs) changes biological rhythm parameters in females. Here, we searched for the mechanisms responsible for these changes. We performed biological rhythm analysis in two experiments: in experiment 1, the mice [C57Bl/6NTac (WT) and M4 MR -/- mice (KO)] were first exposed to a standard LD regime (12/12-h light/dark cycle) for 8 days and then subsequently exposed to constant darkness (for 24 h/day, DD regime) for another 16 days. In experiment 2, the mice (after the standard LD regime) were exposed to the DD regime and to one light pulse (zeitgeber time 14) on day 9. We also detected M1 MRs in brain areas implicated in locomotor biological rhythm regulation. In experiment 1, the biological rhythm activity curves differed: the period (τ, duration of diurnal cycle) was shorter in the DD regime. Moreover, the day mean, mesor (midline value), night mean and their difference were higher in KO animals. The time in which the maximal slope occurred was lower in the DD regime than in the LD regime in both WT and KO but was lower in KO than in WT mice. In experiment 2, there were no differences in biological rhythm parameters between WT and KO mice. The densities of M1 MRs in the majority of areas implicated in locomotor biological rhythm were low. A significant amount of M1 MR was found in the striatum. These results suggest that although core clock output is changed by M4 MR deletion, the structures involved in biological rhythm regulation in WT and KO animals are likely the same, and the most important areas are the striatum, thalamus and intergeniculate leaflet.

Social support modulates subjective and neural responses to sad mental imagery.

Mental imagery related to the recent death of a loved one is associated with intense sadness and distress. Social relations, such as with one's significant other, can regulate negative emotions and provide comfort, but the neural correlates of social comfort are largely unknown. In this functional magnetic resonance imaging study, we examined brain responses to sad mental imagery and how these are modulated by holding hands with one's romantic partner. We found that mental imagery of a recently deceased loved one was associated with increased reactivity in the dorsal striatum, medial prefrontal cortex, anterior and posterior cingulate cortex, thalamus and cerebellum. Holding hands with one's partner as compared to being alone or holding hands with a stranger provided subjective comfort and reduced neural reactivity in the dorsal striatum without affecting the vividness of the imagery. Our findings indicate an important role for the dorsal striatum in sad mental imagery and social comfort and suggest that tactile social support by one's romantic partner regulates subjective distress through other processes than mere distraction from the mental imagery.

Cholinergic Transmission at Muscarinic Synapses in the Striatum Is Driven Equally by Cortical and Thalamic Inputs.

The release of acetylcholine from cholinergic interneurons (ChIs) directly modulates striatal output via muscarinic receptors on medium spiny neurons (MSNs). While thalamic inputs provide strong excitatory input to ChIs, cortical inputs primarily regulate MSN firing. Here, we found that, while thalamic inputs do drive ChI firing, a subset of ChIs responds robustly to stimulation of cortical inputs as well. To examine how input-evoked changes in ChI firing patterns drive acetylcholine release at cholinergic synapses onto MSNs, muscarinic M4-receptor-mediated synaptic events were measured in MSNs overexpressing G-protein gated potassium channels (GIRK2). Stimulation of both cortical and thalamic inputs was sufficient to equally drive muscarinic synaptic events in MSNs, resulting from the broad synaptic innervation of the stimulus-activated ChI population across many MSNs. Taken together, this indicates an underappreciated role for the extensive cholinergic network, in which small populations of ChIs can drive substantial changes in post-synaptic receptor activity across the striatum.

Success and failure of controlling the real-time functional magnetic resonance imaging neurofeedback signal are reflected in the striatum.

INTRODUCTION: Over the last decades, neurofeedback has been applied in variety of research contexts and therapeutic interventions. Despite this extensive use, its neural mechanisms are still under debate. Several scientific advances have suggested that different networks become jointly active during neurofeedback, including regions generally involved in self-regulation, regions related to the specific mental task driving the neurofeedback and regions generally involved in feedback learning (Sitaram et al., 2017, Nature Reviews Neuroscience, 18, 86). METHODS: To investigate the neural mechanisms specific to neurofeedback but independent from general effects of self-regulation, we compared brain activation as measured with functional magnetic resonance imaging (fMRI) across different mental tasks involving gradual self-regulation with and without providing neurofeedback. Ten participants freely chose one self-regulation task and underwent two training sessions during fMRI scanning, one with and one without receiving neurofeedback. During neurofeedback sessions, feedback signals were provided in real-time based on activity in task-related, individually defined target regions. In both sessions, participants aimed at reaching and holding low, medium, or high brain-activation levels in the target region. RESULTS: During gradual self-regulation with neurofeedback, a network of cortical control regions as well as regions implicated in reward and feedback processing were activated. Self-regulation with feedback was accompanied by stronger activation within the striatum across different mental tasks. Additional time-resolved single-trial analysis revealed that neurofeedback performance was positively correlated with a delayed brain response in the striatum that reflected the accuracy of self-regulation. CONCLUSION: Overall, these findings support that neurofeedback contributes to self-regulation through task-general regions involved in feedback and reward processing.

Integrated anatomical and physiological mapping of striatal afferent projections.

The dorsomedial striatum, a key site of reward-sensitive motor output, receives extensive afferent input from cortex, thalamus and midbrain. These projections are integrated by striatal microcircuits containing both spiny projection neurons and local circuit interneurons. To explore target cell specificity of these projections, we compared inputs onto D1-dopamine receptor-positive spiny neurons, parvalbumin-positive fast-spiking interneurons and somatostatin-positive low-threshold-spiking interneurons, using cell type-specific rabies virus tracing and optogenetic-mediated projection neuron recruitment in mice. While the relative proportion of retrogradely labelled projection neurons was similar between target cell types, the convergence of inputs was systematically higher for projections onto fast-spiking interneurons. Rabies virus is frequently used to assess cell-specific anatomical connectivity but it is unclear how this correlates to synaptic connectivity and efficacy. To test this, we compared tracing data with target cell-specific measures of synaptic efficacy for anterior cingulate cortex and parafascicular thalamic projections using novel quantitative optogenetic measures. We found that target-specific patterns of convergence were extensively modified according to region of projection neuron origin and postsynaptic cell type. Furthermore, we observed significant divergence between cell type-specific anatomical connectivity and measures of excitatory synaptic strength, particularly for low-threshold-spiking interneurons. Taken together, this suggests a basic uniform connectivity map for striatal afferent inputs upon which presynaptic-postsynaptic interactions impose substantial diversity of physiological connectivity.

From learning to action: the integration of dorsal striatal input and output pathways in instrumental conditioning.

Considerable evidence suggests that the learning and performance of instrumental actions depend on activity in basal ganglia circuitry; however, these two functions have generally been considered independently. Whereas research investigating the associative mechanisms underlying instrumental conditioning has identified critical cortical and limbic input pathways to the dorsal striatum, the performance of instrumental actions has largely been attributed to activity in the dorsal striatal output pathways, with direct and indirect pathway projection neurons mediating action initiation, perseveration and cessation. Here, we discuss evidence that the dorsal striatal input and basal ganglia output pathways mediate the learning and performance of instrumental actions, respectively, with the dorsal striatum functioning as a transition point. From this perspective, the issue of how multiple striatal inputs are integrated at the level of the dorsal striatum and converted into relatively restricted outputs becomes one of critical significance for understanding how learning is translated into action. So too does the question of how learning signals are modulated by recent experience. We propose that this occurs through recurrent corticostriatothalamic feedback circuits that serve to integrate performance signals by updating ongoing action-related learning.

Motor thalamus supports striatum-driven reinforcement.

Reinforcement has long been thought to require striatal synaptic plasticity. Indeed, direct striatal manipulations such as self-stimulation of direct-pathway projection neurons (dMSNs) are sufficient to induce reinforcement within minutes. However, it's unclear what role, if any, is played by downstream circuitry. Here, we used dMSN self-stimulation in mice as a model for striatum-driven reinforcement and mapped the underlying circuitry across multiple basal ganglia nuclei and output targets. We found that mimicking the effects of dMSN activation on downstream circuitry, through optogenetic suppression of basal ganglia output nucleus substantia nigra reticulata (SNr) or activation of SNr targets in the brainstem or thalamus, was also sufficient to drive rapid reinforcement. Remarkably, silencing motor thalamus-but not other selected targets of SNr-was the only manipulation that reduced dMSN-driven reinforcement. Together, these results point to an unexpected role for basal ganglia output to motor thalamus in striatum-driven reinforcement.

Positive autobiographical memory retrieval reduces temporal discounting.

People generally prefer rewards sooner rather than later. This phenomenon, temporal discounting, underlies many societal problems, including addiction and obesity. One way to reduce temporal discounting is to imagine positive future experiences. Since there is overlap in the neural circuitry associated with imagining future experiences and remembering past events, here we investigate whether recalling positive memories can also promote more patient choice. We found that participants were more patient after retrieving positive autobiographical memories, but not when they recalled negative memories. Moreover, individuals were more impulsive after imagining novel positive scenes that were not related to their memories, showing that positive imagery alone does not drive this effect. Activity in the striatum and temporo parietal junction during memory retrieval predicted more patient choice, suggesting that to the extent that memory recall is rewarding and involves perspective-taking, it influences decision-making. Furthermore, representational similarity in the ventromedial prefrontal cortex between memory recall and decision phases correlated with the behavioral effect across participants. Thus, we have identified a novel manipulation for reducing temporal discounting-remembering the positive past-and have begun to characterize the psychological and neural mechanisms behind it.

Inhibitory Control in the Cortico-Basal Ganglia-Thalamocortical Loop: Complex Regulation and Interplay with Memory and Decision Processes.

We developed a circuit model of spiking neurons that includes multiple pathways in the basal ganglia (BG) and is endowed with feedback mechanisms at three levels: cortical microcircuit, corticothalamic loop, and cortico-BG-thalamocortical system. We focused on executive control in a stop signal task, which is known to depend on BG across species. The model reproduces a range of experimental observations and shows that the newly discovered feedback projection from external globus pallidus to striatum is crucial for inhibitory control. Moreover, stopping process is enhanced by the cortico-subcortical reverberatory dynamics underlying persistent activity, establishing interdependence between working memory and inhibitory control. Surprisingly, the stop signal reaction time (SSRT) can be adjusted by weights of certain connections but is insensitive to other connections in this complex circuit, suggesting novel circuit-based intervention for inhibitory control deficits associated with mental illness. Our model provides a unified framework for inhibitory control, decision making, and working memory.

The Cognitive Architecture of Spatial Navigation: Hippocampal and Striatal Contributions.

Spatial navigation can serve as a model system in cognitive neuroscience, in which specific neural representations, learning rules, and control strategies can be inferred from the vast experimental literature that exists across many species, including humans. Here, we review this literature, focusing on the contributions of hippocampal and striatal systems, and attempt to outline a minimal cognitive architecture that is consistent with the experimental literature and that synthesizes previous related computational modeling. The resulting architecture includes striatal reinforcement learning based on egocentric representations of sensory states and actions, incidental Hebbian association of sensory information with allocentric state representations in the hippocampus, and arbitration of the outputs of both systems based on confidence/uncertainty in medial prefrontal cortex. We discuss the relationship between this architecture and learning in model-free and model-based systems, episodic memory, imagery, and planning, including some open questions and directions for further experiments.

Interactions between default mode and control networks as a function of increasing cognitive reasoning complexity.

Successful performance of challenging cognitive tasks depends on a consistent functional segregation of activity within the default-mode network, on the one hand, and control networks encompassing frontoparietal and cingulo-opercular areas on the other. Recent work, however, has suggested that in some cognitive control contexts nodes within the default-mode and control networks may actually cooperate to achieve optimal task performance. Here, we used functional magnetic resonance imaging to examine whether the ability to relate variables while solving a cognitive reasoning problem involves transient increases in connectivity between default-mode and control regions. Participants performed a modified version of the classic Wason selection task, in which the number of variables to be related is systematically varied across trials. As expected, areas within the default-mode network showed a parametric deactivation with increases in relational complexity, compared with neural activity in null trials. Critically, some of these areas also showed enhanced connectivity with task-positive control regions. Specifically, task-based connectivity between the striatum and the angular gyri, and between the thalamus and right temporal pole, increased as a function of relational complexity. These findings challenge the notion that functional segregation between regions within default-mode and control networks invariably support cognitive task performance, and reveal previously unknown roles for the striatum and thalamus in managing network dynamics during cognitive reasoning.

Exposure to a novel stimulus environment alters patterns of lateralization in avian auditory cortex.

Perceptual filters formed early in development provide an initial means of parsing the incoming auditory stream. However, these filters may not remain fixed, and may be updated by subsequent auditory input, such that, even in an adult organism, the auditory system undergoes plastic changes to achieve a more efficient representation of the recent auditory environment. Songbirds are an excellent model system for experimental studies of auditory phenomena due to many parallels between song learning in birds and language acquisition in humans. In the present study, we explored the effects of passive immersion in a novel heterospecific auditory environment on neural responses in caudo-medial neostriatum (NCM), a songbird auditory area similar to the secondary auditory cortex in mammals. In zebra finches, a well-studied species of songbirds, NCM responds selectively to conspecific songs and contains a neuronal memory for tutor and other familiar conspecific songs. Adult male zebra finches were randomly assigned to either a conspecific or heterospecific auditory environment. After 2, 4 or 9 days of exposure, subjects were presented with heterospecific and conspecific songs during awake electrophysiological recording. The neural response strength and rate of adaptation to the testing stimuli were recorded bilaterally. Controls exposed to conspecific environment sounds exhibited the normal pattern of hemispheric lateralization with higher absolute response strength and faster adaptation in the right hemisphere. The pattern of lateralization was fully reversed in birds exposed to heterospecific environment for 4 or 9 days and partially reversed in birds exposed to heterospecific environment for 2 days. Our results show that brief passive exposure to a novel category of sounds was sufficient to induce a gradual reorganization of the left and right secondary auditory cortices. These changes may reflect modification of perceptual filters to form a more efficient representation of auditory space.

Role of fronto-striatal tract and frontal aslant tract in movement and speech: an axonal mapping study.

Despite a better understanding of their anatomy, the functional role of frontal pathways, i.e., the fronto-striatal tract (FST) and frontal aslant tract (FAT), remains obscure. We studied 19 patients who underwent awake surgery for a frontal glioma (14 left, 5 right) by performing intraoperative electrical mapping of both fascicles during motor and language tasks. Furthermore, we evaluated the relationship between these tracts and the eventual onset of transient postoperative disorders. We also performed post-surgical tract-specific measurements on probabilistic tractography. All patients but one experienced intraoperative inhibition of movement and/or speech during subcortical electrostimulation. On postoperative tractography, the subcortical distribution of stimulated sites corresponded to the spatial course of the FST and/or FAT. Furthermore, we found a significant correlation between postoperative worsening and distances between these tracts and resection cavity. A resection close to the (right or left) FST was correlated with transitory motor initiation disorders (p = 0.026), while a resection close to the left FAT was associated with transient speech initiation disorders (p = 0.003). Moreover, the measurements of average distances between resection cavity and left FAT showed a positive correlation with verbal fluency in both semantic (p = 0.019) and phonemic scores (p = 0.017), while average distances between surgical cavity and left FST showed a positive correlation with verbal fluency scores in both semantic (p = 0.0003) and phonemic modalities (p = 0.037). We suggest that FST and FAT would cooperatively play a role in self-initiated movement and speech, as a part of "negative motor network" involving the pre-supplementary motor area, left inferior frontal gyrus and caudate nucleus.

Salicylate-induced auditory perceptual disorders and plastic changes in nonclassical auditory centers in rats.

Previous studies have shown that sodium salicylate (SS) activates not only central auditory structures, but also nonauditory regions associated with emotion and memory. To identify electrophysiological changes in the nonauditory regions, we recorded sound-evoked local field potentials and multiunit discharges from the striatum, amygdala, hippocampus, and cingulate cortex after SS-treatment. The SS-treatment produced behavioral evidence of tinnitus and hyperacusis. Physiologically, the treatment significantly enhanced sound-evoked neural activity in the striatum, amygdala, and hippocampus, but not in the cingulate. The enhanced sound evoked response could be linked to the hyperacusis-like behavior. Further analysis showed that the enhancement of sound-evoked activity occurred predominantly at the midfrequencies, likely reflecting shifts of neurons towards the midfrequency range after SS-treatment as observed in our previous studies in the auditory cortex and amygdala. The increased number of midfrequency neurons would lead to a relative higher number of total spontaneous discharges in the midfrequency region, even though the mean discharge rate of each neuron may not increase. The tonotopical overactivity in the midfrequency region in quiet may potentially lead to tonal sensation of midfrequency (the tinnitus). The neural changes in the amygdala and hippocampus may also contribute to the negative effect that patients associate with their tinnitus.

Striatal cholinergic cell ablation attenuates L-DOPA induced dyskinesia in Parkinsonian mice.

3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia (LID) is a debilitating side effect of long-term dopamine replacement therapy in Parkinson's Disease. At present, there are few therapeutic options for treatment of LID and mechanisms contributing to the development and maintenance of these drug-induced motor complications are not well understood. We have previously shown that pharmacological reduction of cholinergic tone attenuates the expression of LID in parkinsonian mice with established dyskinesia after chronic L-DOPA treatment. The present study was undertaken to provide anatomically specific evidence for the role of striatal cholinergic interneurons by ablating them before initiation of L-DOPA treatment and determining whether it decreases LID. We used a novel approach to ablate striatal cholinergic interneurons (ChIs) via Cre-dependent viral expression of the diphtheria toxin A subunit (DT-A) in hemiparkinsonian transgenic mice expressing Cre recombinase under control of the choline acetyltransferase promoter. We show that Cre recombinase-mediated DT-A ablation selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated LID without compromising the therapeutic efficacy of L-DOPA. These results provide evidence that ChIs play a key and selective role in LID and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing L-DOPA-induced motor complications in Parkinson's disease.

Cortical and thalamic excitation mediate the multiphasic responses of striatal cholinergic interneurons to motivationally salient stimuli.

Cholinergic interneurons are key components of striatal microcircuits. In primates, tonically active neurons (putative cholinergic interneurons) exhibit multiphasic responses to motivationally salient stimuli that mirror those of midbrain dopamine neurons and together these two systems mediate reward-related learning in basal ganglia circuits. Here, we addressed the potential contribution of cortical and thalamic excitatory inputs to the characteristic multiphasic responses of cholinergic interneurons in vivo. We first recorded and labeled individual cholinergic interneurons in anesthetized rats. Electron microscopic analyses of these labeled neurons demonstrated that an individual interneuron could form synapses with cortical and, more commonly, thalamic afferents. Single-pulse electrical stimulation of ipsilateral frontal cortex led to robust short-latency (<20 ms) interneuron spiking, indicating monosynaptic connectivity, but firing probability progressively decreased during high-frequency pulse trains. In contrast, single-pulse thalamic stimulation led to weak short-latency spiking, but firing probability increased during pulse trains. After initial excitation from cortex or thalamus, interneurons displayed a "pause" in firing, followed by a "rebound" increase in firing rate. Across all stimulation protocols, the number of spikes in the initial excitation correlated positively with pause duration and negatively with rebound magnitude. The magnitude of the initial excitation, therefore, partly determined the profile of later components of multiphasic responses. Upon examining the responses of tonically active neurons in behaving primates, we found that these correlations held true for unit responses to a reward-predicting stimulus, but not to the reward alone, delivered outside of any task. We conclude that excitatory inputs determine, at least in part, the multiphasic responses of cholinergic interneurons under specific behavioral conditions.

Reward-modulated motor information in identified striatum neurons.

It is widely accepted that dorsal striatum neurons participate in either the direct pathway (expressing dopamine D1 receptors) or the indirect pathway (expressing D2 receptors), controlling voluntary movements in an antagonistically balancing manner. The D1- and D2-expressing neurons are activated and inactivated, respectively, by dopamine released from substantia nigra neurons encoding reward expectation. However, little is known about the functional representation of motor information and its reward modulation in individual striatal neurons constituting the two pathways. In this study, we juxtacellularly recorded the spike activity of single neurons in the dorsolateral striatum of rats performing voluntary forelimb movement in a reward-predictable condition. Some of these neurons were identified morphologically by a combination of juxtacellular visualization and in situ hybridization for D1 mRNA. We found that the striatal neurons exhibited distinct functional activations before and during the forelimb movement, regardless of the expression of D1 mRNA. They were often positively, but rarely negatively, modulated by expecting a reward for the correct motor response. The positive reward modulation was independent of behavioral differences in motor performance. In contrast, regular-spiking and fast-spiking neurons in any layers of the motor cortex displayed only minor and unbiased reward modulation of their functional activation in relation to the execution of forelimb movement. Our results suggest that the direct and indirect pathway neurons cooperatively rather than antagonistically contribute to spatiotemporal control of voluntary movements, and that motor information is subcortically integrated with reward information through dopaminergic and other signals in the skeletomotor loop of the basal ganglia.

The brain dynamics of rapid perceptual adaptation to adverse listening conditions.

Listeners show a remarkable ability to quickly adjust to degraded speech input. Here, we aimed to identify the neural mechanisms of such short-term perceptual adaptation. In a sparse-sampling, cardiac-gated functional magnetic resonance imaging (fMRI) acquisition, human listeners heard and repeated back 4-band-vocoded sentences (in which the temporal envelope of the acoustic signal is preserved, while spectral information is highly degraded). Clear-speech trials were included as baseline. An additional fMRI experiment on amplitude modulation rate discrimination quantified the convergence of neural mechanisms that subserve coping with challenging listening conditions for speech and non-speech. First, the degraded speech task revealed an "executive" network (comprising the anterior insula and anterior cingulate cortex), parts of which were also activated in the non-speech discrimination task. Second, trial-by-trial fluctuations in successful comprehension of degraded speech drove hemodynamic signal change in classic "language" areas (bilateral temporal cortices). Third, as listeners perceptually adapted to degraded speech, downregulation in a cortico-striato-thalamo-cortical circuit was observable. The present data highlight differential upregulation and downregulation in auditory-language and executive networks, respectively, with important subcortical contributions when successfully adapting to a challenging listening situation.

Bifrontal tDCS prevents implicit learning acquisition in antidepressant-free patients with major depressive disorder.

The findings for implicit (procedural) learning impairment in major depression are mixed. We investigated this issue using transcranial direct current stimulation (tDCS), a method that non-invasively increases/decreases cortical activity. Twenty-eight age- and gender-matched, antidepressant-free depressed subjects received a single-session of active/sham tDCS. We used a bifrontal setup - anode and cathode over the left and the right dorsolateral prefrontal cortex (DLPFC), respectively. The probabilistic classification-learning (PCL) task was administered before and during tDCS. The percentage of correct responses improved during sham; although not during active tDCS. Procedural or implicit learning acquisition between tasks also occurred only for sham. We discuss whether DLPFC activation decreased activity in subcortical structures due to the depressive state. The deactivation of the right DLPFC by cathodal tDCS can also account for our results. To conclude, active bifrontal tDCS prevented implicit learning in depressive patients. Further studies with different tDCS montages and in other samples are necessary.