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Mental strength and history of winning play an important role in the determination of social dominance. However, the neural circuits mediating these intrinsic and extrinsic factors have remained unclear. Working in mice, we identified a dorsomedial prefrontal cortex (dmPFC) neural population showing “effort”-related firing during moment-to-moment competition in the dominance tube test. Activation or inhibition of the dmPFC induces instant winning or losing, respectively. In vivo optogenetic-based long-term potentiation and depression experiments establish that the mediodorsal thalamic input to the dmPFC mediates long-lasting changes in the social dominance status that are affected by history of winning. The same neural circuit also underlies transfer of dominance between different social contests. These results provide a framework for understanding the circuit basis of adaptive and pathological social behaviors.

Norepinephrine (NE) plays a central role in the acquisition of aversive learning via actions in the lateral nucleus of the amygdala (LA) [1, 2]. However, the function of NE in expression of aversively-conditioned responses has not been established. Given the role of the central nucleus of the amygdala (CeA) in the expression of such behaviors [3–5], and the presence of NE axons projections in this brain nucleus [6], we assessed the effects of NE activity in the CeA on behavioral expression using receptor-specific pharmacology and cell- and projection-specific chemogenetic manipulations. We found that inhibition and activation of locus coeruleus (LC) neurons decreases and increases freezing to aversively conditioned cues, respectively. We then show that locally inhibiting or activating LC terminals in CeA is sufficient to achieve this bidirectional modulation of defensive reactions. These findings support the hypothesis that LC projections to CeA are critical for the expression of defensive responses elicited by conditioned threats.

•Fiber length distribution has the potential to serve as a novel nodal metric for assessing the maturation of topology with age, reflecting the brain's ability to connect remote areas.•The longitudinal changes in fiber length distribution from ages 7 to 8 exhibit region-specific patterns. Specifically, the widespread decrease is driven by a reduction in long-range connections and an increase in short-range connections.•The widespread decrease in fiber length distribution occurred in brain regions responsible for sensory processing, whereas a more localized increase in this metric was observed in regions associated with memory and cognitive control.•This study is the first to provide evidence for the neural structural basis underlying changes in network segregation and integration by employing the fiber length median metric. Environmental and social changes during early school age have a profound impact on brain development. However, it remains unclear how the brains of typically-developing children adjust white matter to optimize network topology during this period. This study proposes fiber length distribution as a novel nodal metric to capture the continuous maturation of brain network. We acquired dMRI data from N = 30 typically developing children in their first year of primary school and a one-year follow-up. We assessed the longitudinal changes in fiber length distribution, characterized by the median length of connected fibers for each brain region. The length median was positively correlated with degree and betweenness centrality, while negatively correlated with clustering coefficient and local efficiency. From ages 7 to 8, we observed significant decreases in length median in the temporal, superior parietal, anterior cingulate, and medial prefrontal cortices, accompanied by a reduction in long-range connections and an increase in short-range connections. Meta-analytic decoding revealed that the widespread decrease in length median occurred in regions responsible for sensory processing, whereas a more localized increase in length median was observed in regions involved in memory and cognitive control. Finally, simulation tests on healthy adults further supported that the decrease in long-range connections and increase in short-range connections contributed to enhanced network segregation and integration, respectively. Our results suggest that the dual process of short- and long-range fiber changes reflects a cost-efficient strategy for optimizing network organization during this critical developmental stage.

Entorhinal cortex transfers multimodal information to hippocampus CA1 neurons via indirect and direct pathways. The authors show that excitatory projections from lateral entorhinal cortex selectively target a subpopulation of morphologically complex, calbindin-expressing pyramidal cells in CA1, forming a distinct direct circuit that is required for olfactory associative learning. Lateral and medial parts of entorhinal cortex (EC) convey nonspatial 'what' and spatial 'where' information, respectively, into hippocampal CA1, via both the indirect EC layer 2→ hippocampal dentate gyrus→CA3→CA1 and the direct EC layer 3→CA1 paths. However, it remains elusive how the direct path transfers distinct information and contributes to hippocampal learning functions. Here we report that lateral EC projection neurons selectively form direct excitatory synapses onto a subpopulation of morphologically complex, calbindin-expressing pyramidal cells (PCs) in the dorsal CA1 (dCA1), while medial EC neurons uniformly innervate all dCA1 PCs. Optogenetically inactivating the distinct lateral EC–dCA1 connections or the postsynaptic dCA1 calbindin-expressing PC activity slows olfactory associative learning. Moreover, optetrode recordings reveal that dCA1 calbindin-expressing PCs develop more selective spiking responses to odor cues during learning. Thus, our results identify a direct lateral EC→dCA1 circuit that is required for olfactory associative learning.

Cortical disinhibition is a common feature of several neuropsychiatric diseases such as schizophrenia, autism and intellectual disabilities. However, the underlying mechanisms are not fully understood. To mimic increased expression of Nrg1 , a schizophrenia susceptibility gene in GABAergic interneurons from patients with schizophrenia, we generated gto Nrg1 mice with overexpression of Nrg1 in GABAergic interneurons. gto Nrg1 mice showed cortical disinhibition at the cellular, synaptic, neural network and behavioral levels. We revealed that the intracellular domain of NRG1 interacts with the cytoplasmic loop 1 of Na v 1.1, a sodium channel critical for the excitability of GABAergic interneurons, and inhibits Na v currents. Intriguingly, activation of GABAergic interneurons or restoring NRG1 expression in adulthood could rescue the hyperactivity and impaired social novelty in gto Nrg1 mice. These results identify mechanisms underlying cortical disinhibition related to schizophrenia and raise the possibility that restoration of NRG1 signaling and GABAergic function is beneficial in certain neuropsychiatric disorders. The molecular and cellular mechanisms of cortical disinhibition as a common feature of many psychiatric diseases are not fully understood. The authors identify an interaction between NRG1 and Nav1.1 sodium channel as a mechanism of how NRG1 modulates the excitability of GABAergic interneurons.

Flexible multichannel electrode arrays (fMEAs) with multiple filaments can be flexibly implanted in various patterns. It is necessary to develop a method for implanting the fMEA in different locations and at various depths based on the recording demands. This study proposed a strategy for reducing the microelectrode volume with integrated packaging. An implantation system was developed specifically for semiautomatic distributed implantation. The feasibility and convenience of the fMEA and implantation platform were verified in rodents. The acute and chronic recording results provied the effectiveness of the packaging and implantation methods. These methods could provide a novel strategy for developing fMEAs with more filaments and recording sites to measure functional interactions across multiple brain regions.

Precise genetic engineering in specific cell types within an intact organism is intriguing yet challenging, especially in a spatiotemporal manner without the interference caused by chemical inducers. Here we engineered a photoactivatable Dre recombinase based on the identification of an optimal split site and demonstrated that it efficiently regulated transgene expression in mouse tissues spatiotemporally upon blue light illumination. Moreover, through a double-floxed inverted open reading frame strategy, we developed a Cre-activated light-inducible Dre (CALID) system. Taking advantage of well-defined cell-type–specific promoters or a well-established Cre transgenic mouse strain, we demonstrated that the CALID system was able to activate endogenous reporter expression for either bulk or sparse labeling of CaMKIIα-positive excitatory neurons and parvalbumin interneurons in the brain. This flexible and tunable system could be a powerful tool for the dissection and modulation of developmental and genetic complexity in a wide range of biological systems.

The neural basis of fear of heights remains largely unknown. In this study, we investigated the fear response to heights in male mice and observed characteristic aversive behaviors resembling human height vertigo. We identified visual input as a critical factor in mouse reactions to heights, while peripheral vestibular input was found to be nonessential for fear of heights. Unexpectedly, we found that fear of heights in naïve mice does not rely on image-forming visual processing by the primary visual cortex. Instead, a subset of neurons in the ventral lateral geniculate nucleus (vLGN), which connects to the lateral/ventrolateral periaqueductal gray (l/vlPAG), drives the expression of fear associated with heights. Additionally, we observed that a subcortical visual pathway linking the superior colliculus to the lateral posterior thalamic nucleus inhibits the defensive response to height threats. These findings highlight a rapid fear response to height threats through a subcortical visual and defensive pathway from the vLGN to the l/vlPAG. The neural basis underlying fear of heights is not well understood. Here the authors identify, in mice, a subcortical route for innate fear of heights, bypassing the primary visual cortex.

The prefrontal cortex (PFC) plays a central role in executive functions and inhibitory control over many cognitive behaviors. Dynamic changes in local field potentials (LFPs), such as gamma oscillation, have been hypothesized to be important for attentive behaviors and modulated by local interneurons such as parvalbumin (PV) cells. However, the precise relationships between the firing patterns of PV interneurons and temporal dynamics of PFC activities remains elusive. In this study, by combining in vivo electrophysiological recordings with optogenetics, we investigated the activities of prefrontal PV interneurons and categorized them into three subtypes based on their distinct firing rates under different behavioral states. Interestingly, all the three subtypes of interneurons showed strong phase-locked firing to cortical high frequency oscillations (HFOs), but not to theta or gamma oscillations, despite of behavior states. Moreover, we showed that sustained optogenetic stimulation (over a period of 10 s) of PV interneurons can consequently modulate the activities of local pyramidal neurons. Interestingly, such optogenetic manipulations only showed moderate effects on LFPs in the PFC. We conclude that prefrontal PV interneurons are consist of several subclasses of cells with distinct state-dependent modulation of firing rates, selectively coupled to HFOs.

The amygdala is a key area in the brain for detecting potential threats or dangers, and further mediating anxiety. However, the neuronal mechanisms of anxiety in the amygdala have not been well characterized. Here we report that in freely-behaving mice, a group of neurons in the basolateral amygdala (BLA) fires tonically under anxiety conditions in both open-field and elevated plus-maze tests. The firing patterns of these neurons displayed a characteristic slow onset and progressively increased firing rates. Specifically, these firing patterns were correlated to a gradual development of anxiety-like behaviors in the open-field test. Moreover, these neurons could be activated by any impoverished environment similar to an open-field; and introduction of both comfortable and uncomfortable stimuli temporarily suppressed the activity of these BLA neurons. Importantly, the excitability of these BLA neurons correlated well with levels of anxiety. These results demonstrate that this type of BLA neuron is likely to represent anxiety and/or emotional values of anxiety elicited by anxiogenic environmental stressors.