Decision-making is an essential cognitive process by which we interact with the external world. However, attempts to understand the neural mechanisms of decision-making are limited by the current available animal models and the technologies that can be applied to them. Here, we build on the renewed interest in using tree shrews ( Tupaia belangeri ) in vision research and provide strong support for them as a model for studying visual perceptual decision-making. Tree shrews learned very quickly to perform a two-alternative forced choice contrast discrimination task, and they exhibited differences in response time distributions depending on the reward and punishment structure of the task. Specifically, they made occasional fast guesses when incorrect responses are punished by a constant increase in the interval between trials. This behavior was suppressed when faster incorrect responses were discouraged by longer intertrial intervals. By fitting the behavioral data with two variants of racing diffusion decisi...

Glucocorticoid signaling influences hippocampal-dependent behavior and vulnerability to stress-related neuropsychiatric disorders. In mice, lifelong overexpression of glucocorticoid receptor (GR) in forebrain excitatory neurons altered exploratory behavior, cognition, and dorsal hippocampal gene expression in adulthood, but whether GR overexpression alters the information encoded by hippocampal neurons is not known. We performed in vivo microendoscopic calcium imaging of 1359 dorsal CA1 pyramidal cells in freely behaving male and female wild-type (WT) and GR-overexpressing (GRov) mice during exploration of a novel open field, where most CA1 neurons are expected to respond to center location and mobility. Most neurons showed sensitivity to center location and/or mobility based on single-neuron calcium amplitude and event rate, but these sensitivity patterns differed between genotypes. GRov neurons were more likely than WT neurons to display center sensitivity and less likely to display mobility sensitivity....

Manipulating the activity of ventral tegmental area (VTA) dopamine (DA) neurons can drive nocifensive reflexes, and their firing rates are reduced following noxious stimuli. However, the pain-relevant inputs to the VTA remain incompletely understood. In this study, we used male and female mice in combination with identified dopamine and GABA neurons in the VTA that receive excitatory inputs from the periaqueductal gray (PAG), a nexus of ascending pain information. We tested whether PAG–VTA synapses undergo functional plasticity in response to a pain model using optical stimulation in conjunction with slice electrophysiology. We found that acute carrageenan inflammation does not significantly affect the strength of excitatory PAG synapses onto VTA DA neurons. However, at the PAG synapses on VTA GABA neurons, the subunit composition of NMDA receptors is altered; the complement of NR2D subunits at synaptic sites appears to be lost. Thus, our data support a model in which injury initially alters synapses on VT...

Intraneuronal chloride concentrations ([Cl−]i) decrease during development resulting in a shift from depolarizing to hyperpolarizing GABA responses via chloride-permeable GABAA receptors. This GABA shift plays a pivotal role in postnatal brain development, and can be strongly influenced by early life experience. Here, we assessed the applicability of the recently developed fluorescent SuperClomeleon (SClm) sensor to examine changes in [Cl−]i using two-photon microscopy in brain slices. We used SClm mice of both sexes to monitor the developmental decrease in neuronal chloride levels in organotypic hippocampal cultures. We could discern a clear reduction in [Cl−]i between day in vitro (DIV)3 and DIV9 (equivalent to the second postnatal week in vivo ) and a further decrease in some cells until DIV22. In addition, we assessed alterations in [Cl−]i in the medial prefrontal cortex (mPFC) of postnatal day (P)9 male SClm mouse pups after early life stress (ELS). ELS was induced by limiting nesting material between...

Absence of presynaptic protein MUNC18-1 (gene: Stxbp1 ) leads to neuronal cell death at an immature stage before synapse formation. Here, we performed transcriptomic and proteomic profiling of immature Stxbp1 knock-out (KO) cells to discover which cellular processes depend on MUNC18-1. Hippocampi of Stxbp1 KO mice showed cell type-specific dysregulation of 2123 transcripts primarily related to synaptic transmission and immune response. To further investigate direct, neuron-specific effects of MUNC18-1 depletion, a proteomic screen was performed on murine neuronal cultures at two developmental timepoints before onset of neuron degeneration. 399 proteins were differentially expressed, which were primarily involved in synaptic function (especially synaptic vesicle exocytosis) and neuron development. We further show that many of the downregulated proteins on loss of MUNC18-1 are normally upregulated during this developmental stage. Thus, absence of MUNC18-1 extensively dysregulates the transcriptome and proteo...

Successful retrieval of a specific item from visual working memory (VWM) depends on the binding of that item to its unique context. Recent functional magnetic resonance imaging studies of VWM manipulating memory set homogeneity have identified an important role for the intraparietal sulcus in context binding, independent of any role in representing stimulus identity. The current study explored whether the contralateral delay activity (CDA), which is an event-related potential (ERP) component derived from posterior electrodes that tracks the amount of information held in VWM, might also be sensitive to context-binding demands. In experiment 1, human participants performed lateralized delayed recognition with memory sets containing one, three, or five items that were drawn from the same category (orientations: “homogeneous”) or from different categories (orientation, color, and luminance: “heterogeneous”). Because the location and identity of the memory probe indicated the item to be retrieved, homogeneous t...

Adaptive control is the online adjustment of behavior to guide and optimize responses after errors or conflict. The neural circuits involved in monitoring and adapting behavioral performance following error are poorly understood. The prefrontal cortex (PFC) plays a critical role in this form of control. However, these brain areas are densely connected with many other regions, and it is unknown which projections are critical for adaptive behavior. Here, we tested the involvement of four distinct dorsal and ventral prefrontal cortical projections to striatal and thalamic target areas in adaptive control. We re-analyzed data from published experiments, using trial-by-trial analyses of behavior in an operant task for attention and impulsivity. We find that male rats slow their responses and perform worse following errors. Moreover, by combining retrograde labeling and chemogenetic silencing, we find that dorsomedial prefrontal pyramidal neurons that project to the lateral nucleus of the mediodorsal thalamus (M...

Primary sensory cortices display functional topography, suggesting that even small cortical volumes may underpin perception of specific stimuli. Traditional loss-of-function approaches have a relatively large radius of effect (>1 mm) and few studies track recovery following loss-of-function perturbations. Consequently, the behavioral necessity of smaller cortical volumes remains unclear. In the mouse primary vibrissal somatosensory cortex (vS1), ‘barrels’ with a radius of ∼150 μm receive input predominantly from a single whisker, partitioning vS1 into a topographic map of well-defined columns. Here, we train animals implanted with a cranial window over vS1 to perform single-whisker perceptual tasks. We then use high-power laser exposure centered on the barrel representing the spared whisker to produce lesions with a typical volume of 1-2 barrels. These columnar-scale lesions impair performance in an object location discrimination task for multiple days without disrupting vibrissal kinematics. Animals with ...

Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin that supports the survival, differentiation and signaling of various neuronal populations. Although it has been well described that expression of BDNF is strongly regulated by neuronal activity, little is known whether regulation of BDNF expression is similar in different brain regions. Here, we focused on this fundamental question using neuronal populations obtained from rat cerebral cortices and hippocampi of both sexes. First, we thoroughly characterized the role of the best-described regulators of BDNF gene – CREB family transcription factors, and show that activity-dependent BDNF expression depends more on CREB and the coactivators CBP and CRTC1 in cortical than in hippocampal neurons. Our data also reveal an important role of CREB in the early induction of BDNF mRNA expression after neuronal activity and only modest contribution after prolonged neuronal activity. We further corroborated our findings at BDNF protein level. To ...

Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the post-synaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of pre-synaptic cannabinoid receptor type 1 (CB1). The eCB system is well-situated to regulate neuronal network properties and coordinate pre- and post-synaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used western blot and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature (>DIV21) cultured rat cortical neurons, and used multielectrode array recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show that BC...