Although sensitizing processes occur earlier, schizophrenia is diagnosed in young adulthood, which suggests that it might involve a pathological transition during late brain development in predisposed individuals. Parvalbumin (PV) interneuron alterations have been noticed, but their role in the disease is unclear. Here we demonstrate that adult LgDel +/À mice, a genetic model of schizophrenia, exhibit PV neuron hypo-recruitment and associated chronic PV neuron plasticity together with network and cognitive deficits. All these deficits can be permanently rescued by chemogenetic activation of PV neurons or D2R antagonist treatments, specifically in the ventral hippocampus (vH) or medial-prefrontal cortex during a late-adolescence-sensitive time window. PV neuron alterations were initially restricted to the hippocampal CA1/subiculum, where they became responsive to treatment in late adolescence. Therefore, progression to disease in schizophrenia-model mice can be prevented by treatments supporting vH-mPFC PV network function during a sensitive time window late in adolescence, suggesting therapeutic strategies to prevent the outbreak of schizophrenia.

Interactions between the mediodorsal thalamus and the prefrontal cortex are critical for cognition. Studies in humans indicate that these interactions may resolve uncertainty in decision-making1, but the precise mechanisms are unknown. Here we identify two distinct mediodorsal projections to the prefrontal cortex that have complementary mechanistic roles in decision-making under uncertainty. Specifically, we found that a dopamine receptor (D2)-expressing projection amplifies prefrontal signals when task inputs are sparse and a kainate receptor (GRIK4) expressing-projection suppresses prefrontal noise when task inputs are dense but conflicting. Collectively, our data suggest that there are distinct brain mechanisms for handling uncertainty due to low signals versus uncertainty due to high noise, and provide a mechanistic entry point for correcting decision-making abnormalities in disorders that have a prominent prefrontal component2–6.

Prefrontal cortical areas mediate flexible adaptive control of behavior, but the specific contributions of individual areas and the circuit mechanisms through which they interact to modulate learning have remained poorly understood. Using viral tracing and pharmacogenetic techniques, we show that prelimbic (PreL) and infralimbic cortex (IL) exhibit reciprocal PreL↔IL layer 5/6 connectivity. In set-shifting tasks and in fear/extinction learning, activity in PreL is required during new learning to apply previously learned associations, whereas activity in IL is required to learn associations alternative to previous ones. IL→PreL connectivity is specifically required during IL-dependent learning, whereas reciprocal PreL↔IL connectivity is required during a time window of 12–14 h after association learning, to set up the role of IL in subsequent learning. Our results define specific and opposing roles of PreL and IL to together flexibly support new learning, and provide circuit evidence that IL-mediated learning of alternative associations depends on direct reciprocal PreL↔IL connectivity.

The cocaine- and amphetamine-regulated transcript (CART) peptidergic system is involved in processing diverse neuronal functions in adult animals, including energy metabolism. Although CART is widely distributed in the brain of a range of vertebrates, the ontogeny of this system has not been explored. The CART-immunoreactive system in the zebrafish central nervous system (CNS) was studied across developmental stages until adulthood. The peptide is expressed as early as 24 hours post fertilization and establishes itself in several discrete areas of the brain and spinal cord as development progresses. The trends in CART ontogeny suggest that it may be involved in the establishment of commissural tracts, typically expressing early but subsequently decaying. CART elements are commonly overrepresented in diverse sensory areas like the olfactory, photic, and acoustico-mechanosensory systems, perhaps indicating a role for the peptide in sensory perception. Key neuroendocrine centers, like the preoptic area, hypothalamus, and pituitary, conspicuously show CART innervations, suggesting functions analogous to those demonstrated in other chordates. Uniquely, the epiphysis also appears to employ CART as a neurotransmitter. The entopeduncular nucleus is a major CART-containing group in the adult teleost forebrain that may participate in glucose sensing. This region responds to glucose in the 15-day larvae, suggesting that the energy status sensing CART circuits is active early in development. The pattern of CART expression in zebrafish suggests conserved evolutionary trends among vertebrate species. Developmental expression profiling reveals putative novel functions and establishes zebrafish as a model to investigate CART function in physiology and development.

The thalamus engages in sensation, action, and cognition, but the structure underlying these functions is poorly understood. Thalamic innervation of associative cortex targets several interneuron types, modulating dynamics and influencing plasticity. Is this structure-function relationship distinct from that of sensory thalamocortical systems? Here, we systematically compared function and structure across a sensory and an associative thalamocortical loop in the mouse. Enhancing excitability of mediodorsal thalamus, an associative structure, resulted in prefrontal activity dominated by inhibition. Equivalent enhancement of medial geniculate excitability robustly drove auditory cortical excitation. Structurally, geniculate axons innervated excitatory cortical targets in a preferential manner and with larger synaptic terminals, providing a putative explanation for functional divergence. The two thalamic circuits also had distinct input patterns, with mediodorsal thalamus receiving innervation from a diverse set of cortical areas. Altogether, our findings contribute to the emerging view of functional diversity across thalamic microcircuits and its structural basis.

Parvalbumin (PV) basket cells are widespread local interneurons that inhibit principal neurons and each other through perisomatic boutons. They enhance network function and regulate local ensemble activities, particularly in the γ range. Organized network activity is critically important for long-term memory consolidation during a late time window 11-15 h after acquisition. Here, we discuss the role of learning-related plasticity in PV neurons for long-term memory consolidation. The plasticity can lead to enhanced (high-PV) or reduced (low-PV) expression of PV/GAD67. High-PV plasticity is induced upon definite reinforced learning in early-born PV basket cells, whereas low-PV plasticity is induced upon provisional reinforced learning in late-born PV basket cells. The plasticity is first detectable 6 h after acquisition, at the end of a time window for memory specification through experience, and is critically important 11-15 h after acquisition for enhanced network activity and longterm memory consolidation. High-and low-PV plasticity appear to regulate activity in distinct local networks of principal neurons and PV basket cells. These findings suggest how flexibility and stability in learning and memory might be implemented through parallel circuits and networks.

Modulation of sensory perception by homeostatic feedback is critical for survival. Gating of sensory inputs by internal states, such as energy availability, enables the animal to issue measured responses, like food-seeking and consumptive behaviors. Olfaction is an important sensory modality in food-seeking behavior providing predictive information on the availability, quality, and associated reward

BackgroundModulation of sensory perception by homeostatic feedback from physiological states is central to innate purposive behaviours. Olfaction is an important predictive modality for feeding-related behaviours and its modulation has been associated with hunger-satiety states. However, the mechanisms mapping internal states to chemosensory processing in order to modify behaviour are poorly understood.ResultsIn the zebrafish olfactory epithelium, a subset of olfactory sensory neurons (OSNs) and the terminal nerve projections express neuropeptide Y (NPY). We find that NPY signalling in the peripheral olfactory system of zebrafish is correlated with its nutritional state and is both necessary and sufficient for the olfactory perception of food related odorants. NPY activity dynamically modulates the microvillar OSN activation thresholds and acts cooperatively with amino acid signalling resulting in a switch-like increase in OSN sensitivity in starved animals. We suggest that cooperative activation of phospholipase C by convergent signalling from NPY and amino acid receptors is central to this heightened sensitivity.ConclusionsThis study provides ethologically relevant, physiological evidence for NPY signalling in peripheral modulation of OSN sensitivity to food-associated amino acid cues. We demonstrate sensory gating directly at the level of OSNs and identify a novel mechanistic framework for tuning olfactory sensitivity to prevailing energy states.