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The mediodorsal nucleus of the thalamus amplifies the functional connectivity of the prefrontal cortex, thereby sustaining cortical representations of rule sets without relaying categorical information. Attention, larger role for thalamus The thalamus has long been associated with relay functions, transferring information to and from cortical processing regions. But recent data suggest there is a large diversity of connectivity between the thalamus and cortex, perhaps also reflecting more functional diversity. Here, Michael Halassa and colleagues find evidence that the thalamus can maintain rule representations and amplify local connectivity to guide attention, but does so without relaying categorical information. This modulation of cortical connectivity suggests that the thalamus may play a larger role in cognitive processes than previously thought. Elsewhere in this issue, Karel Svoboda and colleagues investigate persistent neural activity maintenance for motor planning and show that, in mice, neurons in parts of the thalamus connected to the anterior lateral motor cortex show persistent delay activity that predicted their direction of movement. Although interactions between the thalamus and cortex are critical for cognitive function 1 , 2 , 3 , the exact contribution of the thalamus to these interactions remains unclear. Recent studies have shown diverse connectivity patterns across the thalamus 4 , 5 , but whether this diversity translates to thalamic functions beyond relaying information to or between cortical regions 6 is unknown. Here we show, by investigating the representation of two rules used to guide attention in the mouse prefrontal cortex (PFC), that the mediodorsal thalamus sustains these representations without relaying categorical information. Specifically, mediodorsal input amplifies local PFC connectivity, enabling rule-specific neural sequences to emerge and thereby maintain rule representations. Consistent with this notion, broadly enhancing PFC excitability diminishes rule specificity and behavioural performance, whereas enhancing mediodorsal excitability improves both. Overall, our results define a previously unknown principle in neuroscience; thalamic control of functional cortical connectivity. This function, which is dissociable from categorical information relay, indicates that the thalamus has a much broader role in cognition than previously thought.

The authors trained mice to attend to or suppress vision based on behavioral context and show, through novel and established techniques, that changes in visual gain rely on tunable feedforward inhibition of visual thalamus via innervating thalamic reticular neurons; these findings introduce a subcortical model of attention in which modality-specific thalamic reticular subnetworks mediate top-down and context-dependent control of sensory selection. Subcortical sensory selection The prefrontal cortex is thought to regulate attention to sensory stimuli through top-down control of sensory cortical areas. Here, Michael Halassa and colleagues trained mice to attend to the appropriate stimulus by selecting between two competing auditory and visual stimuli. Performance on this task required the prelimbic cortex, but not the anterior cingulate cortex (ACC) or the lateral orbitofrontal cortex (OFC), and involved prelimbic cortex interactions with the visual thalamic reticular nucleus (visTRN) rather than with sensory cortex. They provide evidence that the visTRN controls visual thalamic gain through feedforward inhibition of the lateral geniculate nucleus, thereby selecting the appropriate input for further processing. These findings support a subcortical model of sensory selection in which modality-specific thalamic reticular subnetworks mediate top-down control of sensory thalamic gain. How the brain selects appropriate sensory inputs and suppresses distractors is unknown. Given the well-established role of the prefrontal cortex (PFC) in executive function 1 , its interactions with sensory cortical areas during attention have been hypothesized to control sensory selection 2 , 3 , 4 , 5 . To test this idea and, more generally, dissect the circuits underlying sensory selection, we developed a cross-modal divided-attention task in mice that allowed genetic access to this cognitive process. By optogenetically perturbing PFC function in a temporally precise window, the ability of mice to select appropriately between conflicting visual and auditory stimuli was diminished. Equivalent sensory thalamocortical manipulations showed that behaviour was causally dependent on PFC interactions with the sensory thalamus, not sensory cortex. Consistent with this notion, we found neurons of the visual thalamic reticular nucleus (visTRN) to exhibit PFC-dependent changes in firing rate predictive of the modality selected. visTRN activity was causal to performance as confirmed by bidirectional optogenetic manipulations of this subnetwork. Using a combination of electrophysiology and intracellular chloride photometry, we demonstrated that visTRN dynamically controls visual thalamic gain through feedforward inhibition. Our experiments introduce a new subcortical model of sensory selection, in which the PFC biases thalamic reticular subnetworks to control thalamic sensory gain, selecting appropriate inputs for further processing.

Significance A modular 3D brain-like cortical tissue is constructed with silk protein-based scaffold and ECM composite and primary cortical neurons. This tissue responds in vitro with biochemical and electrophysiological outcomes, mimicking observations of brain homeostasis and mechanical injury responses. The brain remains one of the most important but least understood tissues in our body, in part because of its complexity as well as the limitations associated with in vivo studies. Although simpler tissues have yielded to the emerging tools for in vitro 3D tissue cultures, functional brain-like tissues have not. We report the construction of complex functional 3D brain-like cortical tissue, maintained for months in vitro, formed from primary cortical neurons in modular 3D compartmentalized architectures with electrophysiological function. We show that, on injury, this brain-like tissue responds in vitro with biochemical and electrophysiological outcomes that mimic observations in vivo. This modular 3D brain-like tissue is capable of real-time nondestructive assessments, offering previously unidentified directions for studies of brain homeostasis and injury.

During low arousal states such as drowsiness and sleep, cortical neurons exhibit rhythmic slow wave activity associated with periods of neuronal silence. Slow waves are locally regulated, and local slow wave dynamics are important for memory, cognition, and behaviour. While several brainstem structures for controlling global sleep states have now been well characterized, a mechanism underlying fast and local modulation of cortical slow waves has not been identified. Here, using optogenetics and whole cortex electrophysiology, we show that local tonic activation of thalamic reticular nucleus (TRN) rapidly induces slow wave activity in a spatially restricted region of cortex. These slow waves resemble those seen in sleep, as cortical units undergo periods of silence phase-locked to the slow wave. Furthermore, animals exhibit behavioural changes consistent with a decrease in arousal state during TRN stimulation. We conclude that TRN can induce rapid modulation of local cortical state. We usually think of sleep as a global state: that the entire brain is either asleep or awake. However, recent evidence has suggested that smaller regions of the brain can show sleep-like activity while the rest of the brain remains awake. It is not clear why or how these sleep-like patterns of brain activity appear, and whether they are related to the drowsy behaviour that occurs when one is about to fall asleep. Lewis, Voigts et al. investigated how this process works in mice using a technique called optogenetics. This technique makes it possible to genetically engineer mice so that the activity of particular areas of the brain can be switched on or off by light. Lewis, Voigts et al. used light to stimulate different regions of the brain and tracked the resulting brain activity using tiny electrodes that are capable of detecting the activity of individual neurons. The experiments show that stimulating one part of a deep brain structure called the thalamic reticular nucleus causes just one small part of the brain to switch from being awake to producing sleep-like brain wave patterns. When a larger area is stimulated, the whole brain switches into this sleep-like pattern. Stimulation of the thalamic reticular nucleus also caused the animals to become drowsy and they were more likely to fall asleep, which suggests that sleep-like activity in small parts of the brain may contribute to drowsiness. Lewis, Voigts et al.’s findings identify a brain switch that can influence whether an animal is awake or asleep. Importantly, they show that sleep can be independently controlled in small brain regions, and that the thalamic reticular nucleus contains a ‘map’ that allows it to induce sleep in just one region, or across the whole brain. Memories are strengthened during sleep, so the next challenge is to study whether the thalamic reticular nucleus influences memory formation. The findings also suggest that further study of this brain region may be useful for understanding how the sleep and awake states are controlled by particular neurons.

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.

Increased activity of dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens of rats during a ‘decision’ period reflects a ‘loss’ outcome of the previous decision, and predicts a subsequent safe choice; by artificially increasing the activity of D2R neurons during the decision period, risk-seeking rats could be converted to risk-avoiding rats. 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. PTCHD1 deletions in neurodevelopmental disorder Disruption of the PTCHD1 gene in humans has been associated with attention deficits, intellectual disability, and autism spectrum disorders, but the brain areas involved are not known. Guoping Feng and colleagues report that Ptchd1 deletion in mice attenuated thalamic reticular nucleus (TRN) activity by reducing calcium-dependent potassium currents (SK). Mice with TRN-restricted Ptchd1 deletion had fragmented sleep, attention deficits and hyperactivity, which could be rescued by an SK channel activator. By contrast, mice with global Ptchd1 deletion had learning impairments, hyper-aggression and motor defects, which were insensitive to the SK channel activator. These findings suggest that a TRN deficit may underlie several impairments associated with neurodevelopmental disorders, and identify possible therapeutic targets for individuals with PTCHD1 deletion.

While localizing sensory and motor deficits is one of the cornerstones of clinical neurology, behavioral and cognitive deficits in psychiatry remain impervious to this approach. In psychiatry, major challenges include the relative subtlety by which neural circuits are perturbed, and the limited understanding of how basic circuit functions relate to thought and behavior. Neurodevelopmental disorders offer a window to addressing the first challenge given their strong genetic underpinnings, which can be linked to biological mechanisms. Such links have benefited from genetic modeling in the mouse, and in this review we highlight how this small mammal is now allowing us to crack neural circuits as well. We review recent studies of mouse thalamus, discussing how they revealed general principles that may underlie human perception and attention. Controlling the magnitude (gain) of thalamic sensory responses is a mechanism of attention, and the mouse has enabled its functional dissection at an unprecedented resolution. Further, modeling human genetic neurodevelopmental disease in the mouse has shown how diminished thalamic gain control can lead to attention deficits. This breaks new ground in how we untangle the complexity of psychiatric diseases; by making thalamic circuits accessible to mechanistic dissection; the mouse has not only taught us how they fundamentally work, but also how their dysfunction can be precisely mapped onto behavioral and cognitive deficits. Future studies promise even more progress, with the hope that principled targeting of identified thalamic circuits can be uniquely therapeutic.

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.

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.

Understanding the neural mechanisms behind short-term memory (STM) errors is crucial for unraveling cognitive processes and addressing related deficits in neuropsychiatric disorders. This study investigates whether STM errors result from misrepresentation of sensory information or a decay in these representations over time. Utilizing 2-photon calcium imaging in the posterior parietal cortex (PPC) of mice engaged in a delayed match-to-sample task, we identified a subset of PPC neurons exhibiting both directional and temporal selectivity. Contrary to the idea that STM errors primarily stem from mis-encoding during the sample phase, our findings indicate that these errors are more closely associated with a drift in neural activity during the delay period. This drift results in a gradual shift away from the correct representation, ultimately leading to incorrect behavioral responses. These results emphasize the importance of maintaining stable neural representations in the PPC for accurate STM. Our findings also suggest that targeting PPC activity stabilization during delay periods could be a potential therapeutic strategy for mitigating cognitive impairments in disorders like schizophrenia.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Some parts of the method have been revised.