Thalamic Neurons Research Articles

Patterned Stimulation of the Chrimson Opsin in Glutamatergic Motor Thalamus Neurons Improves Forelimb Akinesia in Parkinsonian Rats

Parkinson’s disease (PD) is a motor disorder charactertised by altered neural activity throughout the basal ganglia-thalamocortical circuit. Electrical deep brain stimulation (DBS) is efficacious in alleviating motor symptoms, but has several notable side-effects, most likely reflecting the non-specific nature of electrical stimulation and/or the brain regions targeted. We determined whether specific optogenetic activation of glutamatergic motor thalamus (Mthal) neurons alleviated forelimb akinesia in a chronic rat model of PD. Parkinsonian rats (unilateral 6-hydroxydopamine injection) were injected with an adeno-associated viral vector (AAV5-CaMKII-Chrimson-GFP) to transduce glutamatergic Mthal neurons with the red-shifted Chrimson opsin. Optogenetic stimulation with orange light at 15 Hz tonic and a physiological pattern, previously recorded from a Mthal neuron in a control rat, significantly increased forelimb use in the reaching test (p < 0.01). Orange light theta burst stimulation, 15 Hz and control reaching patterns significantly reduced akinesia (p < 0.0001) assessed by the step test. In contrast, forelimb use in the cylinder test was unaffected by orange light stimulation with any pattern. Blue light (control) stimulation failed to alter behaviours. Activation of Chrimson using complex patterns in the Mthal may be an alternative treatment to recover movement in PD. These vector and opsin changes are important steps towards translating optogenetic stimulation to humans.

Sustained Activation of the Anterior Thalamic Neurons with Low Doses of Kainic Acid Boosts Hippocampal Neurogenesis.

Adult hippocampal neurogenesis is prone to modulation by several intrinsic and extrinsic factors. The anterior nucleus (AN) of the thalamus has extensive connections with the hippocampus, and stimulation of this region may play a role in altering neurogenesis. We have previously shown that electrical stimulation of the AN can substantially boost hippocampal neurogenesis in adult rats. Here, we performed selective unilateral chemical excitation of the cell bodies of the AN as it offers a more specific and sustained stimulation when compared to electrical stimulation. Our aim is to investigate the long-term effects of KA stimulation of the AN on baseline hippocampal proliferation of neural stem cells and neurogenesis. Continuous micro-perfusion of very low doses of kainic acid (KA) was administered into the right AN for seven days. Afterwards, adult male rats received 5'-bromo-2'-deoxyuridine (BrdU) injections (200 mg/kg, i.p) and were euthanized at either one week or four weeks post micro-perfusion. Open field and Y-maze tests were performed before euthanasia. The KA stimulation of the AN evoked sustained hippocampal neurogenesis that was associated with improved spatial memory in the Y-maze test. Administering dexamethasone prior to and simultaneously with the KA stimulation decreased both the hippocampal neurogenesis and the improved spatial recognition memory previously seen in the Y-maze test. These results suggest that hippocampal neurogenesis may be a downstream effect of stimulation in general, and of excitation of the cell bodies of the AN in particular, and that stimulation of that area improves spatial memory in rats.

A Role for Thalamic Projection GABAergic Neurons in Circadian Responses to Light.

The thalamus is an important hub for sensory information and participates in sensory perception, regulation of attention, arousal and sleep. These functions are executed primarily by glutamatergic thalamocortical neurons that extend axons to the cortex and initiate cortico-thalamocortical connectional loops. However, the thalamus also contains projection GABAergic neurons that do not extend axons toward the cortex. Here, we have harnessed recent insight into the development of the intergeniculate leaflet (IGL) and the ventral lateral geniculate nucleus (LGv) to specifically target and manipulate thalamic projection GABAergic neurons in female and male mice. Our results show that thalamic GABAergic neurons of the IGL and LGv receive retinal input from diverse classes of retinal ganglion cells (RGCs) but not from the M1 intrinsically photosensitive retinal ganglion cell (ipRGC) type. We describe the synergistic role of the photoreceptor melanopsin and the thalamic neurons of the IGL/LGv in circadian entrainment to dim light. We identify a requirement for the thalamic IGL/LGv neurons in the rapid changes in vigilance states associated with circadian light transitions.SIGNIFICANCE STATEMENT The intergeniculate leaflet (IGL) and ventral lateral geniculate nucleus (LGv) are part of the extended circadian system and mediate some nonimage-forming visual functions. Here, we show that each of these structures has a thalamic (dorsal) as well as prethalamic (ventral) developmental origin. We map the retinal input to thalamus-derived cells in the IGL/LGv complex and discover that while RGC input is dominant, this is not likely to originate from M1ipRGCs. We implicate thalamic cells in the IGL/LGv in vigilance state transitions at circadian light changes and in overt behavioral entrainment to dim light, the latter exacerbated by concomitant loss of melanopsin expression.

Reconsideration of the firing loop models for dystonia and Parkinson's disease

AbstractParkinson's disease (PD) is a hypokinetic movement disorder with degeneration of dopaminergic and other neurons, whereas dystonia is a hyperkinetic movement disorder caused by various pathogenesis, that is, sporadic, genetic, stroke, brain injury, and other diseases, such as PD. Dopamine receptor 1 (D1R) antagonist and dopamine receptor 2 (D2R) antagonist induce dystonic symptom in monkey. Consistently, D1R antagonist and D2R antagonist decrease locomotion in mice. Moreover, D1R knock‐out (KO) mice and D2R KO mice show motor deficits. In humans, dopa‐responsive dystonia (DRD) is caused by genetically defective dopamine (DA) synthesis. DYT1 dystonia and genetic mouse models show decreased striatal D1R and D2R. Therefore, PD, pharmacological dystonia models, DRD and DYT1 dystonia, have defective DA pathways. Firing of globus pallidus internus (GPi) neurons is increased in PD and dystonia with local anesthesia. However, the ordinary firing loop model cannot explain how defective DA pathways induce dystonia. PD shows thalamic neurodegeneration, whereas PD with dystonia has relatively intact thalamic neurons. Since thalamic GABAergic interneurons are innervated by GPi GABAergic neurons, here I propose to add thalamic GABAergic interneurons between GPi GABAergic neurons and thalamic glutamatergic neurons as thalamic inverse pathway for healthy condition and dystonia, whereas thalamic ordinary pathway due to degeneration of thalamic GABAergic interneurons is suitable to PD. On the contrary, PD with dystonia has both thalamic ordinary and inverse pathways. Although precise thalamic circuits have not been elucidated, discrepancy in the ordinary firing loop model for dystonia seems to be solved by the thalamic switch from dystonia to PD.

Convergence of bilateral auditory midbrain inputs on neurons in the auditory thalamus of chicken.

In the avian ascending auditory pathway, the nucleus mesencephalicus lateralis pars dorsalis (MLd; the auditory midbrain center) receives inputs from virtually all lower brainstem auditory nuclei and sends outputs bilaterally to the nucleus ovoidalis (Ov; the auditory thalamic nucleus). Axons from part of the MLd terminate in a particular domain of Ov, thereby suggesting a formation of segregated pathways point-to-point from lower brainstem nuclei via MLd to the thalamus. However, it has not yet been demonstrated whether any spatial clustering of thalamic neurons that receive inputs from specific domains of MLd exists. Ov neurons receive input from bilateral MLds; however, the degree of laterality has not been reported yet. In this study, we injected a recombinant avian adeno-associated virus, a transsynaptic anterograde vector into the MLd of the chick, and analyzed the distribution of labeled postsynaptic neurons on both sides of the Ov. We found that fluorescent protein-labeled neurons on both sides of the Ov were clustered in domains corresponding to subregions of the MLd. The laterality of projections was calculated as the ratio of neurons labeled by comparing ipsilateral to contralateral projections from the MLd, and it was 1.86 on average, thereby indicating a slight ipsilateral projection dominance. Bilateral inputs from different subdomains of the MLd converged on several single Ov neurons, thereby implying a possibility of a de novo binaural processing of the auditory information in the Ov.

The altered sensitivity of acute stress induced anxiety-related behaviors by modulating insular cortex-paraventricular thalamus-bed nucleus of the stria terminalis neural circuit

The dysregulation of neuronal networks contributes to the etiology of psychiatric diseases, including anxiety. However, the neural circuits underlying anxiety symptoms remain unidentified. We observed acute restraint stress activating excitatory neurons in the paraventricular thalamus (PVT). Activation of PVT neurons caused anxious behaviors, whereas suppression of PVT neuronal activity induced an anxiolytic effect, achieved by using a chemogenetic method. Moreover, we found that the PVT neurons showed plentiful neuronal projections to the bed nucleus of the stria terminalis (BNST). Activation of PVT-BNST neural projections increased the susceptibility of stress-induced anxiety-related behaviors, and inhibition of this neural circuit produced anxiolysis. The insular cortex (IC) is an important upstream region projecting to PVT. Activation of IC-PVT neuronal projections enhanced susceptibility to stress induced anxious behaviors. Inhibiting this neural circuit suppressed anxious behaviors. Moreover, anterograde monosynaptic tracing results showed that the IC exerts strong neuronal projections to PVT, forming synaptic connections with its neurons, and these neurons throw extensive neuronal fibers to form synapse with BNST neurons. Finally, our results showed that ablation of neurons in PVT receiving monosynaptic input from IC attenuated the anxiety-related phenotypes induced by activating IC neurons. Lesions of the neurons in BNST synaptic origination from PVT blocked the anxiety-related phenotypes induced by activating PVT neurons. Our findings indicate that the PVT is a crucial anxiety-regulating nucleus, and the IC-PVT-BNST neural projection is an essential pathway affecting anxiety morbidity and treatment.

Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency.

Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.

Neural Representation of Intraoral Olfactory and Gustatory Signals by the Mediodorsal Thalamus in Alert Rats.

The mediodorsal thalamus is a multimodal region involved in a variety of cognitive behaviors, including olfactory attention, odor discrimination, and the hedonic perception of flavors. Although the mediodorsal thalamus forms connections with principal regions of the olfactory and gustatory networks, its role in processing olfactory and gustatory signals originating from the mouth remains unclear. Here, we recorded single-unit activity in the mediodorsal thalamus of behaving female rats during the intraoral delivery of individual odors, individual tastes, and odor-taste mixtures. Our results are the first to demonstrate that neurons in the mediodorsal thalamus dynamically encode chemosensory signals originating from the mouth. This chemoselective population is broadly tuned, exhibits excited and suppressed responses, and responds to odor-taste mixtures differently than an odor or taste alone. Furthermore, a subset of chemoselective neurons encodes the palatability-related features of tastes and may represent associations between previously experienced odor-taste pairs. Our results further demonstrate the multidimensionality of the mediodorsal thalamus and provide additional evidence of its involvement in processing chemosensory information important for ingestive behaviors.SIGNIFICANCE STATEMENT The perception of food relies on the concurrent processing of olfactory and gustatory signals originating from the mouth. The mediodorsal thalamus is a higher-order thalamic nucleus involved in a variety of chemosensory-dependent behaviors and connects the olfactory and gustatory cortices with the prefrontal cortex. However, it is unknown how neurons in the mediodorsal thalamus process intraoral chemosensory signals. Using tetrode recordings in alert rats, our results are the first to show that neurons in the mediodorsal thalamus dynamically represent olfactory and gustatory signals from the mouth. Our findings are consistent with the mediodorsal thalamus being a key node between sensory and prefrontal cortical areas for processing chemosensory information underlying ingestive behavior.

A Combinatorial Input Landscape in the "Higher-Order Relay" Posterior Thalamic Nucleus.

All pathways targeting the thalamus terminate directly onto the thalamic projection cells. As these cells lack local excitatory interconnections, their computations are fundamentally defined by the type and local convergence patterns of the extrinsic inputs. These two key variables, however, remain poorly defined for the "higher-order relay" (HO) nuclei that constitute most of the thalamus in large-brained mammals, including humans. Here, we systematically analyzed the input landscape of a representative HO nucleus of the mouse thalamus, the posterior nucleus (Po). We examined in adult male and female mice the neuropil distribution of terminals immunopositive for markers of excitatory or inhibitory neurotransmission, mapped input sources across the brain and spinal cord and compared the intranuclear distribution and varicosity size of axons originated from each input source. Our findings reveal a complex landscape of partly overlapping input-specific microdomains. Cortical layer (L)5 afferents from somatosensory and motor areas predominate in central and ventral Po but are relatively less abundant in dorsal and lateral portions of the nucleus. Excitatory inputs from the trigeminal complex, dorsal column nuclei (DCN), spinal cord and superior colliculus as well as inhibitory terminals from anterior pretectal nucleus and zona incerta (ZI) are each abundant in specific Po regions and absent from others. Cortical L6 and reticular thalamic nucleus terminals are evenly distributed across Po. Integration of specific input motifs by particular cell subpopulations may be commonplace within HO nuclei and favor the emergence of multiple, functionally diverse input-output subnetworks.SIGNIFICANCE STATEMENT Because thalamic projection neurons lack local interconnections, their output is essentially determined by the kind and convergence of the long-range inputs that they receive. Fragmentary evidence suggests that these parameters may vary within the "higher-order relay" (HO) nuclei that constitute much of the thalamus, but such variation has not been systematically analyzed. Here, we mapped the origin and local convergence of all the extrinsic inputs reaching the posterior nucleus (Po), a typical HO nucleus of the mouse thalamus by combining multiple neuropil labeling and axon tracing methods. We report a complex mosaic of partly overlapping input-specific domains within Po. Integration of different input motifs by specific cell subpopulations in HO nuclei may favor the emergence of multiple, computationally specialized thalamocortical subnetworks.

Study protocol: Effects of active versus passive recharge burst spinal cord stimulation on pain experience in persistent spinal pain syndrome type 2: a multicentre randomized trial (BURST-RAP study)

BackgroundSpinal cord stimulation (SCS) has shown to be an effective treatment for patients with persistent spinal pain syndrome type 2 (PSPS Type 2). The method used to deliver electrical charge in SCS is important. One such method is burst stimulation. Within burst stimulation, a recharge pattern is used to prevent buildup of charge in stimulated tissues. Two variations of burst waveforms are currently in use: one that employs active recharge and one that uses passive recharge. It has been suggested that differences exist between active and passive recharge paradigms related to both efficacy of pain relief and their underlying mechanism of action. Active recharge has been shown to activate both the medial spinal pathway, engaging cortical sensorimotor areas involved in location and intensity of pain, and lateral pathway, reaching brain areas involved with cognitive-emotional aspects of pain. Passive recharge has been suggested to act via modulation of thalamic neurons, which fire in a similar electrical pattern, and thereby modulate activity in various cortical areas including those related to motivational and emotional aspects of pain. The objective of this randomized clinical trial is to assess and compare the effect of active versus passive recharge Burst SCS on a wide spectrum of pain in PSPS Type 2 patients.MethodsThis multicentre randomized clinical trial will take place in 6 Dutch hospitals. PSPS Type 2 patients (n=94) will be randomized into a group receiving either active or passive recharge burst. Following a successful trial period, patients are permanently implanted. Patients complete the Pain Catastrophizing Scale (PCS) (primary outcome at 6 months), Numeric Pain Rating Scale (NRS), Patient Vigilance and Awareness Questionnaire (PVAQ), Hospital Anxiety and Depression Scale (HADS), Quality of Life (EQ-5D), Oswestery Disability Index (ODI), Patient Global Impression of Change (PGIC) and painDETECT questionnaires (secondary outcomes) at baseline, after trial, 1, 3, 6 and 12 months following implantation.DiscussionThe BURST-RAP trial protocol will shed light on possible clinical differences and effectivity of pain relief, including emotional-motivational aspects between active and passive burst SCS in PSPS Type 2 patients.Trial registrationClinicalTrials.gov registration: NCT05421273. Registered on 16 June 2022. Netherlands Trial Register NL9194. Registered on 23 January 2021.

Intensity-Varied Closed-Loop Noise Stimulation for Oscillation Suppression in the Parkinsonian State.

This work explores the effectiveness of the intensity-varied closed-loop noise stimulation on the oscillation suppression in the Parkinsonian state. Deep brain stimulation (DBS) is the standard therapy for Parkinson's disease (PD), but its effects need to be improved. The noise stimulation has compelling results in alleviating the PD state. However, in the open-loop control scheme, the noise stimulation parameters cannot be self-adjusted to adapt to the amplitude of the synchronized neuronal activities in real time. Thus, based on the delayed-feedback control algorithm, an intensity-varied closed-loop noise stimulation strategy is proposed. Based on a computational model of the basal ganglia (BG) that can present the intrinsic properties of the BG neurons and their interactions with the thalamic neurons, the proposed stimulation strategy is tested. Simulation results show that the noise stimulation suppresses the pathological beta (12-35 Hz) oscillations without any new rhythms in other bands compared with traditional high-frequency DBS. The intensity-varied closed-loop noise stimulation has a more profound role in removing the pathological beta oscillations and improving the thalamic reliability than open-loop noise stimulation, especially for different PD states. And the closed-loop noise stimulation enlarges the parameter space of the delayed-feedback control algorithm due to the randomness of noise signals. We also provide a theoretical analysis of the effective parameter domain of the delayed-feedback control algorithm by simplifying the BG model to an oscillator model. This exploration may guide a new approach to treating PD by optimizing the noise-induced improvement of the BG dysfunction.

Fitting of TC model according to key parameters affecting Parkinson's state based on improved particle swarm optimization algorithm

Biophysical models contain a large number of parameters, while the spiking characteristics of neurons are related to a few key parameters. For thalamic neurons, relay reliability is an important characteristic that affects Parkinson's state. This paper proposes a method to fit key parameters of the model based on the spiking characteristics of neurons, and improves the traditional particle swarm optimization algorithm. That is, a nonlinear concave function and a Logistic chaotic mapping are combined to adjust the inertia weight of particles to avoid the particle falling into a local optimum in the search process or appearing premature convergence. In this paper, three parameters that play an important role in Parkinson's state of the thalamic cell model are selected and fitted by the improved particle swarm optimization algorithm. Using the fitted parameters to reconstruct the neuron model can predict the spiking trajectories well, which verifies the effectiveness of the fitting method. By comparing the fitting results with other particle swarm optimization algorithms, it is shown that the proposed particle swarm optimization algorithm can better avoid local optima and converge to the optimal values quickly.

Presynaptic supervision of cortical spine dynamics in motor learning.

In mammalian neocortex, learning triggers the formation and turnover of new postsynaptic spines on pyramidal cell dendrites. However, the biological principles of spine reorganization during learning remain elusive because the identity of their presynaptic neuronal partners is unknown. Here, we show that two presynaptic neural circuits supervise distinct programs of spine dynamics to execute learning. We imaged spine dynamics in motor cortex during learning and performed post hoc identification of their afferent presynaptic neurons. New spines that appeared during learning formed small transient contacts with corticocortical neurons that were eliminated on skill acquisition. In contrast, persistent spines with axons from thalamic neurons were formed and enlarged. These results suggest that pyramidal cell dendrites in motor cortex use a neural circuit division of labor during skill learning, with dynamic teaching contacts from top-down intracortical axons followed by synaptic memory formation driven by thalamic axons. Dual spine supervision may govern diverse skill learning in the neocortex.

Phosphatidylcholine and Phosphatidylserine Uniquely Modify the Secondary Structure of α-Synuclein Oligomers Formed in Their Presence at the Early Stages of Protein Aggregation.

Abrupt aggregation of α-synuclein (α-Syn) leads to a formation of highly toxic protein oligomers. These aggregates are the underlying molecular cause of an onset of the irreversible degeneration of dopaminergic neurons in midbrain, hypothalamus, and thalamus, a pathology known as Parkinson's disease. The transient nature of oligomers, as well as their structural and morphological heterogeneity, limits the use of cryo-electron microscopy and solid-state NMR, classical tools of structural biology, for elucidation of their secondary structure. Despite this limitation, numerous pieces of experimental evidence suggest that phospholipids can uniquely alter the structure and toxicity of oligomers. In this study, we utilize an innovative nano-infrared imaging technique, also known as atomic force microscopy infrared (AFM-IR) spectroscopy, to examine the structure of individual α-Syn oligomers grown in the presence of phosphatidylcholine (α-Syn:PC) and phosphatidylserine (α-Syn:PS). We determined the amount of the parallel and the antiparallel β-sheets, as well as the amount the α-helix and the unordered protein, in the secondary structure of α-Syn:PC and α-Syn:PS formed at day 2 (D2), 8 (D8), and 15 (D15) after initiation of protein aggregation. We found a gradual decrease in the amount of the parallel β-sheet in both α-Syn:PC and α-Syn:PS from D2 to D15 together with an increase in the α-helix and the unordered protein secondary structure. We infer that this is due to the presence of lipids in the structure of oligomers that prevent an expansion of the parallel β-sheet upon interaction of the oligomers with monomeric α-Syn.

AgRP neurons control structure and function of the medial prefrontal cortex.

Hypothalamic agouti-related peptide and neuropeptide Y-expressing (AgRP) neurons have a critical role in both feeding and non-feeding behaviors of newborn, adolescent, and adult mice, suggesting their broad modulatory impact on brain functions. Here we show that constitutive impairment of AgRP neurons or their peripubertal chemogenetic inhibition resulted in both a numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice. These changes were accompanied by alteration of oscillatory network activity in mPFC, impaired sensorimotor gating, and altered ambulatory behavior that could be reversed by the administration of clozapine, a non-selective dopamine receptor antagonist. Theobserved AgRP effects are transduced to mPFC in part via dopaminergic neurons in the ventral tegmental area and may also be conveyedby medial thalamic neurons. Our results unmasked a previously unsuspected role for hypothalamic AgRP neurons in control ofneuronal pathways that regulate higher-order brain functions during development and in adulthood.

State-Dependent Modulation of Activity in Distinct Layer 6 Corticothalamic Neurons in Barrel Cortex of Awake Mice.

Layer 6 corticothalamic (L6 CT) neurons are in a strategic position to control sensory input to the neocortex, yet we understand very little about their functions. Apart from studying their anatomic, physiological, and synaptic properties, most recent efforts have focused on the activity-dependent influences CT cells can exert on thalamic and cortical neurons through causal optogenetic manipulations. However, few studies have attempted to study them during behavior. To address this gap, we performed juxtacellular recordings from optogenetically identified CT neurons in whisker-related primary somatosensory cortex (wS1) of awake, head-fixed mice (either sex) free to rest quietly or self-initiate bouts of whisking and locomotion. We found a rich diversity of response profiles exhibited by CT cells. Their spiking patterns were either modulated by whisking-related behavior (∼28%) or not (∼72%). Whisking-responsive neurons exhibited both increases (activated-type) and decreases in firing rates (suppressed-type) that aligned with whisking onset better than locomotion. We also encountered responsive neurons with preceding modulations in firing rate before whisking onset. Overall, whisking better explained these changes in rates than overall changes in arousal. Whisking-unresponsive CT cells were generally quiet, with many having low spontaneous firing rates (sparse-type) and others being completely silent (silent-type). Remarkably, the sparse firing CT population preferentially spiked at the state transition point when pupil diameter constricted, and the mouse entered quiet wakefulness. Thus, our results demonstrate that L6 CT cells in wS1 show diverse spiking patterns, perhaps subserving distinct functional roles related to precisely timed responses during complex behaviors and transitions between discrete waking states.SIGNIFICANCE STATEMENT Layer 6 corticothalamic neurons provide a massive input to the sensory thalamus and local connectivity within cortex, but their role in thalamocortical processing remains unclear because of difficulty accessing and isolating their activity. Although several recent optogenetic studies reveal that the net influence of corticothalamic actions, suppression versus enhancement, depends critically on the rate these neurons fire, the factors that influence their spiking are poorly understood, particularly during wakefulness. Using the well-established Ntsr1-Cre line to target this elusive population in the whisker somatosensory cortex of awake mice, we found that corticothalamic neurons show diverse state-related responses and modulations in firing rate. These results suggest separate corticothalamic populations can differentially influence thalamocortical excitability during rapid state transitions in awake, behaving animals.

Visual recognition of social signals by a tectothalamic neural circuit

Social affiliation emerges from individual-level behavioural rules that are driven by conspecific signals1–5. Long-distance attraction and short-distance repulsion, for example, are rules that jointly set a preferred interanimal distance in swarms6–8. However, little is known about their perceptual mechanisms and executive neural circuits3. Here we trace the neuronal response to self-like biological motion9,10, a visual trigger for affiliation in developing zebrafish2,11. Unbiased activity mapping and targeted volumetric two-photon calcium imaging revealed 21 activity hotspots distributed throughout the brain as well as clustered biological-motion-tuned neurons in a multimodal, socially activated nucleus of the dorsal thalamus. Individual dorsal thalamus neurons encode local acceleration of visual stimuli mimicking typical fish kinetics but are insensitive to global or continuous motion. Electron microscopic reconstruction of dorsal thalamus neurons revealed synaptic input from the optic tectum and projections into hypothalamic areas with conserved social function12–14. Ablation of the optic tectum or dorsal thalamus selectively disrupted social attraction without affecting short-distance repulsion. This tectothalamic pathway thus serves visual recognition of conspecifics, and dissociates neuronal control of attraction from repulsion during social affiliation, revealing a circuit underpinning collective behaviour.

Influence of Rat Central Thalamic Neurons on Foraging Behavior in a Hazardous Environment.

Foraging entails a complex balance between approach and avoidance alongside sensorimotor and homeostatic processes under the control of multiple cortical and subcortical areas. Recently, it has become clear that several thalamic nuclei located near the midline regulate motivated behaviors. However, one midline thalamic nucleus that projects to key nodes in the foraging network, the central medial thalamic nucleus (CMT), has received little attention so far. Therefore, the present study examined CMT contributions to foraging behavior using inactivation and unit recording techniques in male rats. Inactivation of CMT or the basolateral amygdala (BLA) with muscimol abolished the normally cautious behavior of rats in the foraging task. Moreover, CMT neurons showed large but heterogeneous activity changes during the foraging task, with many neurons decreasing or increasing their discharge rates, with a modest bias for the latter. A generalized linear model revealed that the nature (inhibitory vs excitatory) and relative magnitude of the activity modulations seen in CMT neurons differed markedly from those of principal BLA cells but were very similar to those of fast-spiking BLA interneurons. Together, these findings suggest that CMT is an important regulator of foraging behavior. In the Discussion, we consider how CMT is integrated into the network of structures that regulate foraging.SIGNIFICANCE STATEMENT Foraging entails a complex balance between approach and avoidance alongside sensorimotor and homeostatic processes under the control of multiple cortical and subcortical areas. Although the central medial thalamic nucleus (CMT) is connected to many nodes in this network, its role in the regulation of foraging behavior has not been investigated so far. Here, we examined CMT contributions to foraging behavior using inactivation and unit recording techniques. We found that CMT inactivation abolishes the normally cautious foraging behavior of rats and that CMT neurons show large but heterogeneous changes in firing rates during the foraging task. Together, these results suggest that CMT is an important regulator of foraging behavior.

Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models

Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls.Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.

Anterior thalamic circuits crucial for working memory

Alterations in the structure and functional connectivity of anterior thalamic nuclei (ATN) have been linked to reduced cognition during aging. However, ATN circuits that contribute to higher cognitive functions remain understudied. We found that the anteroventral (AV) subdivision of ATN is necessary specifically during the maintenance phase of a spatial working memory task. This function engages the AV→parasubiculum (PaS)→entorhinal cortex (EC) circuit. Aged mice showed a deficit in spatial working memory, which was associated with a decrease in the excitability of AV neurons. Activation of AV neurons or the AV→PaS circuit in aged mice was sufficient to rescue their working memory performance. Furthermore, rescued aged mice showed improved behavior-induced neuronal activity in prefrontal cortex (PFC), a critical site for working memory processes. Although the direct activation of PFC neurons in aged mice also rescued their working memory performance, we found that these animals exhibited increased levels of anxiety, which was not the case for AV→PaS circuit manipulations in aged mice. These results suggest that targeting AV thalamus in aging may not only be beneficial for cognitive functions but that this approach may have fewer unintended effects compared to direct PFC manipulations.