Thalamic Inhibition: Diverse Sources, Diverse Scales.

The thalamus is the major source of cortical inputs shaping sensation, action, and cognition. Thalamic circuits are targeted by two major inhibitory systems: the thalamic reticular nucleus (TRN) and extrathalamic inhibitory (ETI) inputs. A unifying framework of how these systems operate is currently lacking. Here, we propose that TRN circuits are specialized to exert thalamic control at different spatiotemporal scales. Local inhibition of thalamic spike rates prevails during attentional selection, whereas global inhibition more likely prevails during sleep. In contrast, the ETI (arising from basal ganglia, zona incerta (ZI), anterior pretectum, and pontine reticular formation) provides temporally precise and focal inhibition, impacting spike timing. Together, these inhibitory systems allow graded control of thalamic output, enabling thalamocortical operations to dynamically match ongoing behavioral demands

Thalamic reticular impairment underlies attention deficit in Ptchd1Y/− mice

Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect one in six children in the USA. Recently, gene mutations in patched domain containing 1 (PTCHD1) have been found in ∼1% of patients with ID and ASD. Individuals with PTCHD1 deletion show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is probably critical for normal development, the connection between its deletion and the ensuing behavioural defects is poorly understood. Here we report that during early post-natal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamocortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity through mechanisms involving small conductance calcium-dependent potassium currents (SK). TRN-restricted deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channel activity. Global Ptchd1 deletion recapitulates learning impairment, hyper-aggression, and motor defects, all of which are insensitive to SK pharmacological targeting and not found in the TRN-restricted deletion mouse. This study maps clinically relevant behavioural phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.Simons Foundation Autism Research Initiative (Grant 307913)National Institutes of Health (U.S.) (Grant R01MH097104)National Institute of Mental Health (U.S.) (Grant R01MH097104)National Institutes of Health (U.S.) (Grant R01MH107680

Empathic accuracy and aggression in couples: Individual and dyadic links

This study examined links between intimate partner aggression and empathic accuracy – how accurately partners can read one another’s emotions – during highly affective moments from couples’ (N = 109) video recall of laboratory-based discussions of upsetting events. Less empathic accuracy between partners was generally related to higher levels of aggression by both partners. More specific patterns emerged based on the type of aggression and emotion being expressed. Women’s poorer ability to read their partners’ vulnerable and positive emotions was linked to both men’s and women’s greater physical and psychological aggression. Moreover, women’s inaccuracy in reading their partner’s hostility was linked to women’s greater psychological aggression towards the men. Men’s inaccuracy in reading their partner’s hostility was linked to women’s (not men’s) greater physical and psychological aggression. Findings suggest important nuances in the links between empathic inaccuracy and aggression, and implications for prevention and treatment of partner aggression are discussed

The thalamus in psychosis spectrum disorder

Psychosis spectrum disorder (PSD) affects 1% of the world population and results in a lifetime of chronic disability, causing devastating personal and economic consequences. Developing new treatments for PSD remains a challenge, particularly those that target its core cognitive deficits. A key barrier to progress is the tenuous link between the basic neurobiological understanding of PSD and its clinical phenomenology. In this perspective, we focus on a key opportunity that combines innovations in non-invasive human neuroimaging with basic insights into thalamic regulation of functional cortical connectivity. The thalamus is an evolutionary conserved region that forms forebrain-wide functional loops critical for the transmission of external inputs as well as the construction and update of internal models. We discuss our perspective across four lines of evidence: First, we articulate how PSD symptomatology may arise from a faulty network organization at the macroscopic circuit level with the thalamus playing a central coordinating role. Second, we discuss how recent animal work has mechanistically clarified the properties of thalamic circuits relevant to regulating cortical dynamics and cognitive function more generally. Third, we present human neuroimaging evidence in support of thalamic alterations in PSD, and propose that a similar “thalamocortical dysconnectivity” seen in pharmacological imaging (under ketamine, LSD and THC) in healthy individuals may link this circuit phenotype to the common set of symptoms in idiopathic and drug-induced psychosis. Lastly, we synthesize animal and human work, and lay out a translational path for biomarker and therapeutic development

State-Dependent Architecture of Thalamic Reticular Subnetworks

Behavioral state is known to influence interactions between thalamus and cortex, which are important for sensation, action, and cognition. The thalamic reticular nucleus (TRN) is hypothesized to regulate thalamo-cortical interactions, but the underlying functional architecture of this process and its state dependence are unknown. By combining the first TRN ensemble recording with psychophysics and connectivity-based optogenetic tagging, we found reticular circuits to be composed of distinct subnetworks. While activity of limbic-projecting TRN neurons positively correlates with arousal, sensory-projecting neurons participate in spindles and show elevated synchrony by slow waves during sleep. Sensory-projecting neurons are suppressed by attentional states, demonstrating that their gating of thalamo-cortical interactions is matched to behavioral state. Bidirectional manipulation of attentional performance was achieved through subnetwork-specific optogenetic stimulation. Together, our findings provide evidence for differential inhibition of thalamic nuclei across brain states, where the TRN separately controls external sensory and internal limbic processing facilitating normal cognitive function.National Institute of Neurological Disorders and Stroke (U.S.) (NIH Pathway to Independence Career Award K99 NS 078115)Brain & Behavior Research Foundation (Young Investigator Award)National Institutes of Health (U.S.) ( Transformative R01 Award TR01-GM10498)National Institutes of Health (U.S.) (Grant R01-MH061976

Design and Fabrication of Ultralight Weight, Adjustable Multi-electrode Probes for Electrophysiological Recordings in Mice

The number of physiological investigations in the mouse, mus musculus, has experienced a recent surge, paralleling the growth in methods of genetic targeting for microcircuit dissection and disease modeling. The introduction of optogenetics, for example, has allowed for bidirectional manipulation of genetically-identified neurons, at an unprecedented temporal resolution. To capitalize on these tools and gain insight into dynamic interactions among brain microcircuits, it is essential that one has the ability to record from ensembles of neurons deep within the brain of this small rodent, in both head-fixed and freely behaving preparations. To record from deep structures and distinct cell layers requires a preparation that allows precise advancement of electrodes towards desired brain regions. To record neural ensembles, it is necessary that each electrode be independently movable, allowing the experimenter to resolve individual cells while leaving neighboring electrodes undisturbed. To do both in a freely behaving mouse requires an electrode drive that is lightweight, resilient, and highly customizable for targeting specific brain structures. A technique for designing and fabricating miniature, ultralight weight, microdrive electrode arrays that are individually customizable and easily assembled from commercially available parts is presented. These devices are easily scalable and can be customized to the structure being targeted; it has been used successfully to record from thalamic and cortical regions in a freely behaving animal during natural behavior.Simons FoundationNational Institute of Neurological Disorders and Stroke (U.S.) (NIH Pathway to Independence Career Award)National Institutes of Health (U.S.

Sequence learning in Associative Neuronal-Astrocytic Network

The neuronal paradigm of studying the brain has left us with limitations in both our understanding of how neurons process information to achieve biological intelligence and how such knowledge may be translated into artificial intelligence and its most brain-derived branch, neuromorphic computing. Overturning our fundamental assumptions of how the brain works, the recent exploration of astrocytes is revealing that these long-neglected brain cells dynamically regulate learning by interacting with neuronal activity at the synaptic level. Following recent experimental evidence, we designed an associative, Hopfield-type, neuronal-astrocytic network and analyzed the dynamics of the interaction between neurons and astrocytes. We show that astrocytes were sufficient to trigger transitions between learned memories in the neuronal component of the network. Further, we mathematically derived the timing of the transitions that was governed by the dynamics of the calcium-dependent slow-currents in the astrocytic processes. Overall, we provide a brain-morphic mechanism for sequence learning that is inspired by, and aligns with, recent experimental findings. To evaluate our model, we emulated astrocytic atrophy and showed that memory recall becomes significantly impaired after a critical point of affected astrocytes was reached. This brain-inspired and brain-validated approach supports our ongoing efforts to incorporate non-neuronal computing elements in neuromorphic information processing.Comment: 8 pages, 5 figure

Prefrontal Computation as Active Inference

The prefrontal cortex is vital for a range of cognitive processes, including working memory, attention, and decision-making. Notably, its absence impairs the performance of tasks requiring the maintenance of information through a delay period. In this paper, we formulate a rodent task—which requires maintenance of delay-period activity—as a Markov decision process and treat optimal task performance as an (active) inference problem. We simulate the behavior of a Bayes optimal mouse presented with 1 of 2 cues that instructs the selection of concurrent visual and auditory targets on a trial-by-trial basis. Formulating inference as message passing, we reproduce features of neuronal coupling within and between prefrontal regions engaged by this task. We focus on the micro-circuitry that underwrites delay-period activity and relate it to functional specialization within the prefrontal cortex in primates. Finally, we simulate the electrophysiological correlates of inference and demonstrate the consequences of lesions to each part of our in silico prefrontal cortex. In brief, this formulation suggests that recurrent excitatory connections—which support persistent neuronal activity—encode beliefs about transition probabilities over time. We argue that attentional modulation can be understood as the contextualization of sensory input by these persistent beliefs

Sensory and cortical activation of distinct glial cell subtypes in the somatosensory thalamus of young rats

The rodent ventrobasal (VB) thalamus receives sensory inputs from the whiskers and projects to the cortex, from which it receives reciprocal excitatory afferents. Much is known about the properties and functional roles of these glutamatergic inputs to thalamocortical neurons in the VB, but no data are available on how these afferents can affect thalamic glial cells. In this study, we used combined electrophysiological recordings and intracellular calcium ([Ca2+]i) imaging to investigate glial cell responses to synaptic afferent stimulation. VB thalamus glial cells can be divided into two groups based on their [Ca2+]i and electrophysiological responses to sensory and corticothalamic stimulation. One group consists of astrocytes, which stain positively for S100B and preferentially load with SR101, have linear current–voltage relations and low input resistance, show no voltage-dependent [Ca2+]i responses, but express mGluR5-dependent [Ca2+]i transients following stimulation of the sensory and/or corticothalamic excitatory afferent pathways. Cells of the other glial group, by contrast, stain positively for NG2, and are characterized by high input resistance, the presence of voltage-dependent [Ca2+]i elevations and voltage-gated inward currents. There were no synaptically induced [Ca2+]i elevations in these cells under control conditions. These results show that thalamic glial cell responses to synaptic input exhibit different properties to those of thalamocortical neurons. As VB astrocytes can respond to synaptic stimulation and signal to neighbouring neurons, this glial cell organization may have functional implications for the processing of somatosensory information and modulation of behavioural state-dependent thalamocortical network activities

Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents : an in vitro study

Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state