Highlights • We introduce a framework in which the thalamus controls functional connectivity within and across cortical areas. • Thalamic control of cortical connectivity can occur without relaying ...or specifying categorical content. • Thalamic construction of a functional cortical network underlies the generation of a directed arousal state. • Directed arousal is an intermediate level of cognitive description that bridges general arousal to precise control of sensorimotor transformations.
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.
The frequency of human social and emotional disorders varies significantly between males and females. We have recently reported that oxytocin receptor interneurons (OxtrINs) modulate female ...sociosexual behavior. Here, we show that, in male mice, OxtrINs regulate anxiety-related behaviors. We demonstrate that corticotropin-releasing-hormone-binding protein (CRHBP), an antagonist of the stress hormone CRH, is specifically expressed in OxtrINs. Production of CRHBP blocks the CRH-induced potentiation of postsynaptic layer 2/3 pyramidal cell activity of male, but not female, mice, thus producing an anxiolytic effect. Our data identify OxtrINs as critical for modulation of social and emotional behaviors in both females and males and reveal a molecular mechanism that acts on local medial prefrontal cortex (mPFC) circuits to coordinate responses to OXT and CRH. They suggest that additional studies of the impact of the OXT/OXTR and CRHBP/CRH pathways in males and females will be important in development of gender-specific therapies.
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•Activation of OxtrINs is anxiolytic in males and prosocial in females•OxtrINs specifically express CRHBP, an inhibitor of the stress hormone CRH•CRHBP blocks activation of layer 2/3 pyramidal cells by CRH only in males•OxtrINs in the mPFC coordinate sexually dimorphic social/emotional behaviors
A population of oxytocin-responsive neurons blocks anxiety-related behaviors in male, but not female, mice, suggesting a basis for sex-specific differences observed in some emotional disorders.
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, its interactions with ...sensory cortical areas during attention have been hypothesized to control sensory selection. 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.
•Tasks are needed to engage brain networks relevant to specific cognitive functions.•Recent approaches enable the control of activity in selected neurons during behavior.•Advanced techniques make it ...possible to simultaneously record thousands of neurons.•Novel analysis methods have improved assessment of neural and behavioral data.•Combining these approaches in mice will reveal new insight into cognitive functions.
Understanding how cognitive functions arise from computations occurring in the brain requires the ability to measure and perturb neural activity while the relevant circuits are engaged for specific cognitive processes. Rapid technical advances have led to the development of new approaches to transiently activate and suppress neuronal activity as well as to record simultaneously from hundreds to thousands of neurons across multiple brain regions during behavior. To realize the full potential of these approaches for understanding cognition, however, it is critical that behavioral conditions and stimuli are effectively designed to engage the relevant brain networks. Here, we highlight recent innovations that enable this combined approach. In particular, we focus on how to design behavioral experiments that leverage the ever-growing arsenal of technologies for controlling and measuring neural activity in order to understand cognitive functions.
The heterogeneity of exosomal populations has hindered our understanding of their biogenesis, molecular composition, biodistribution and functions. By employing asymmetric flow field-flow ...fractionation (AF4), we identified two exosome subpopulations (large exosome vesicles, Exo-L, 90-120 nm; small exosome vesicles, Exo-S, 60-80 nm) and discovered an abundant population of non-membranous nanoparticles termed 'exomeres' (~35 nm). Exomere proteomic profiling revealed an enrichment in metabolic enzymes and hypoxia, microtubule and coagulation proteins as well as specific pathways, such as glycolysis and mTOR signalling. Exo-S and Exo-L contained proteins involved in endosomal function and secretion pathways, and mitotic spindle and IL-2/STAT5 signalling pathways, respectively. Exo-S, Exo-L and exomeres each had unique N-glycosylation, protein, lipid, DNA and RNA profiles and biophysical properties. These three nanoparticle subsets demonstrated diverse organ biodistribution patterns, suggesting distinct biological functions. This study demonstrates that AF4 can serve as an improved analytical tool for isolating extracellular vesicles and addressing the complexities of heterogeneous nanoparticle subpopulations.
We have recently developed a novel method for the affinity purification of the complete suite of translating mRNA from genetically labeled cell populations. This method permits comprehensive ...quantitative comparisons of the genes employed by each specific cell type. We provide a detailed description of tools for analysis of data generated with this and related methodologies. An essential question that arises from these data is how to identify those genes that are enriched in each cell type relative to all others. Genes relatively specifically employed by a cell type may contribute to the unique functions of that cell, and thus may become useful targets for development of pharmacological tools for cell-specific manipulations. We describe here a novel statistic, the specificity index, which can be used for comparative quantitative analysis to identify genes enriched in specific cell populations across a large number of profiles. This measure correctly predicts in situ hybridization patterns for many cell types. We apply this measure to a large survey of CNS cell-specific microarray data to identify those genes that are significantly enriched in each population Data and algorithms are available online (www.bactrap.org).
Abstract Maladaptive forms of self-focus, such as rumination, are considered transdiagnostic factors that contribute to depressive and anxiety symptoms. However, no or few studies have explored the ...possibility that adaptive forms of self-focus can also be a common factor that is negatively associated with depressive and anxiety symptoms. To test this possibility, we first examined the psychometric properties of a scale measuring adaptive forms of self-focus (the Self-Reflection and Insight Scale) on Japanese undergraduates ( n = 117). We replicated the two-factor structure of the scale: (a) self-reflection, which is a tendency to focus purposefully on self for self-regulation, and (b) insight, which is a sense of clear self-understanding. Second, we tested our specific hypothesis that these two factors negatively predict a common factor of depressive and anxiety symptoms. The results of structural equation modeling showed that insight (but not self-reflection) has a significant negative association with a latent variable that explains both depressive and anxiety symptoms. Furthermore, this common-factor model explained the data better than a control model in which insight predicts depressive and anxiety symptoms individually. These results suggest that (lack of) insight plays an important role in psychological (mal)adjustment as a shared process in depressive and anxiety symptoms.
Adaptive behavior is supported by context-dependent cognitive control that enables stable and flexible sensorimotor transformations. Impairments in this type of control are often attributed to ...dysfunction in the prefrontal cortex (PFC). However, the underlying circuit principles of PFC function that support cognitive control have remained elusive. While the complex, diverse responses of PFC neurons to cognitive variables have been studied both from the perspective of individual cell activity and overall population dynamics, these two levels have often been investigated separately. This review discusses two specific cell groups, context/brain state responsive interneuron subtypes and output decoder neurons, that might bridge conceptual frameworks derived from these two research approaches. I highlight the unique properties and functions of these cell groups and discuss how future studies leveraging their features are likely to provide a new understanding of PFC dynamics combining single-neuron and network perspectives.
Past research has suggested that self-insight functions as a genuine factor to enhance psychological adjustment. However, because most of the previous studies had used a cross-sectional design, a ...prospective study was warranted to establish the temporal and causal relationship between self-insight and depressive symptoms. Another important issue was that there seems to be a moderator that influences the adaptive function of self-insight. Stein and Grant (2014) suggested that positive self-evaluation mediates the association between self-insight and well-being. This result could imply that self-insight does not lead to well-being with negative self-evaluation. In this study, therefore, we conducted a longitudinal questionnaire survey to examine the prospective effect of self-insight on future depressive symptoms with self-complexity as a putative moderator. A complete dataset of 93 Japanese undergraduates was analyzed. The prospective analysis showed a significant moderating role of negative self-complexity in the associations among self-insight, depressive symptoms, and stress; people with high self-insight and low negative self-complexity were less likely to be influenced by stressors, whereas those with high self-insight and high negative self-complexity showed significant increases in depressive symptoms after stressful experiences. These findings implicate that the adaptive effect of self-insight can be conditional depending on the extent of negative self-complexity.
•Self-insight has been considered as a factor that enhances psychological adjustment.•However, we found that the adaptive effect of self-insight was conditional.•Self-insight with high negative self-complexity was related to increased depression.
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