Faculty Bibliography

In this issue of Neuron, Collins et al. (2018) delineate the functional circuit architecture connecting the prefrontal cortex with two major thalamic territories, the mediodorsal and ventromedial.

Diagnoses of behavioral disorders such as autism spectrum disorder and schizophrenia are based on symptomatic descriptions that have been difficult to connect to mechanism. Although psychiatric genetics provide insight into the genetic underpinning of such disorders, with a majority of cases explained by polygenic factors, it remains difficult to design rational treatments. In this review, we highlight the value of understanding neural circuit function both as an intermediate level of explanatory description that links gene to behavior and as a pathway for developing rational diagnostics and therapeutics for behavioral disorders. As neural circuits perform hierarchically organized computational functions and give rise to network-level processes (e.g., macroscopic rhythms and goal-directed or homeostatic behaviors), correlated network-level deficits may indicate perturbation of a specific circuit. Therefore, identifying such correlated deficits or a circuit endophenotype would provide a mechanistic point of entry, enhancing both diagnosis and treatment of a given behavioral disorder. We focus on a circuit endophenotype of the thalamic reticular nucleus (TRN) and how its impairment in neurodevelopmental disorders gives rise to a correlated set of readouts across sleep and attention. Because TRN neurons express several disorder-relevant genes identified through genome-wide association studies, exploring the consequences of different TRN disruptions may be of broad translational significance.

Cognition can be conceptualized as a set of algorithmic control functions whose real-time deployment determines how an organism stores and uses information to guide thought and action. A subset of these functions is required for goal-directed selection and amplification of sensory signals-broadly referred to as attention-and for its flexible control and its interaction with processes such as working memory and decision making. While the contribution of recurrent cortical microcircuits to cognition has been extensively studied, the role of the thalamus is just beginning to be elucidated. Here we highlight recent studies across rodents and primates showing how thalamus contributes to attentional control. In addition to high-fidelity information relay to or between cortical regions, thalamic circuits shift and sustain functional interactions within and across cortical areas. This thalamic process enables rapid coordination of spatially segregated cortical computations, thereby constructing task-relevant functional networks. Because such function may be critical for cognitive flexibility, clarifying its mechanisms will likely expand our basic understanding of cognitive control and its perturbation in disease.

A substantial portion of our sensory experience happens during active behaviors such as walking around or paying attention. How do sensory systems work during such behaviors? Neural processing in sensory systems can be shaped by behavior in multiple ways ranging from a modulation of responsiveness or sharpening of tuning to a dynamic change of response properties or functional connectivity. Here, we review recent findings on the modulation of sensory processing during active behaviors in different systems: insect vision, rodent thalamus, and rodent sensory cortices. We discuss the circuit-level mechanisms that might lead to these modulations and their potential role in sensory function. Finally, we highlight the open questions and future perspectives of this exciting new field.

The thalamus is an evolutionarily conserved structure with extensive reciprocal connections to cortical regions. While its role in transmitting sensory signals is well-studied, its broader engagement in cognition is unclear. In this review, we discuss evidence that the thalamus regulates functional connectivity within and between cortical regions, determining how a cognitive process is implemented across distributed cortical microcircuits. Within this framework, thalamic circuits do not necessarily determine the categorical content of a cognitive process (e.g., sensory details in feature-based attention), but rather provide a route by which task-relevant cortical representations are sustained and coordinated. Additionally, thalamic control of cortical connectivity bridges general arousal to the specific processing of categorical content, providing an intermediate level of cognitive and circuit description that will facilitate mapping neural computations onto thought and behavior.

Although interactions between the thalamus and cortex are critical for cognitive function, the exact contribution of the thalamus to these interactions remains unclear. Recent studies have shown diverse connectivity patterns across the thalamus, but whether this diversity translates to thalamic functions beyond relaying information to or between cortical regions 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.

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.Molecular Psychiatry advance online publication, 11 October 2016; doi:10.1038/mp.2016.183.

Rapid eye movement (REM) sleep onset is triggered by disinhibition of cholinergic neurons in the pons. During REM sleep, the brain exhibits prominent activity in the 5-8 Hz (theta) frequency range. How REM sleep onset and theta waves are regulated is poorly understood. Astrocytes, a non-neuronal cell type in the brain, respond to cholinergic signals by elevating their intracellular Ca2+ concentration. The goal of this study was to assess the sleep architecture of mice with attenuated IP3 mediated Ca2+ signaling in astrocytes. Vigilance states and cortical electroencephalograph power were measured in wild type mice and mice with attenuated IP3/Ca2+ signaling. Attenuating IP3/Ca2+ signaling specifically in astrocytes caused mice to spend more time in REM sleep and enter this state more frequently during their inactive phase. These mice also exhibited greater power in the theta frequency range. These data suggest a role for astrocytic IP3/Ca2+ signaling in modulating REM sleep and the associated physiological state of the cortex.

Independently adjustable multielectrode arrays are routinely used to interrogate neuronal circuit function, enabling chronic in vivo monitoring of neuronal ensembles in freely behaving animals at a single-cell, single spike resolution. Despite the importance of this approach, its widespread use is limited by highly specialized design and fabrication methods. To address this, we have developed a Scalable, Lightweight, Integrated and Quick-to-assemble multielectrode array platform. This platform additionally integrates optical fibers with independently adjustable electrodes to allow simultaneous single unit recordings and circuit-specific optogenetic targeting and/or manipulation. In current designs, the fully assembled platforms are scalable from 2 to 32 microdrives, and yet range 1-3 g, light enough for small animals. Here, we describe the design process starting from intent in computer-aided design, parameter testing through finite element analysis and experimental means, and implementation of various applications across mice and rats. Combined, our methods may expand the utility of multielectrode recordings and their continued integration with other tools enabling functional dissection of intact neural circuits.

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.