The nucleus accumbens shell (NAcSh) receives extensive monoaminergic input from multiple midbrain structures. However, little is known how norepinephrine (NE) modulates NAc circuit dynamics. Using a dynamic electrophysiological approach with optogenetics, pharmacology, and drugs acutely restricted by tethering (DART), we explored microcircuit-specific neuromodulatory mechanisms recruited by NE signaling in the NAcSh of parvalbumin (PV)-specific reporter mice. Surprisingly, NE had little direct effect on modulation of synaptic input at medium spiny projection neurons (MSNs). In contrast, we report that NE transmission selectively modulates glutamatergic synapses onto PV-expressing fast-spiking interneurons (PV-INs) by recruiting postsynaptically-localized α2-adrenergic receptors (ARs). The synaptic effects of α2-AR activity decrease PV-IN-dependent feedforward inhibition onto MSNs evoked via optogenetic stimulation of cortical afferents to the NAcSh. These findings provide insight into a new circuit motif i...

Natural stimuli display spatiotemporal characteristics that typically vary over orders of magnitude, and their encoding by sensory neurons remains poorly understood. We investigated population coding of highly heterogeneous natural electrocommunication stimuli in Apteronotus leptorhynchus of either sex. Neuronal activities were positively correlated with one another in the absence of stimulation, and correlation magnitude decayed with increasing distance between recording sites. Under stimulation, we found that correlations between trial-averaged neuronal responses (i.e., signal correlations) were positive and higher in magnitude for neurons located close to another, but that correlations between the trial-to-trial variability (i.e., noise correlations) were independent of physical distance. Overall, signal and noise correlations were independent of stimulus waveform as well as of one another. To investigate how neuronal populations encoded natural electrocommunication stimuli, we considered a nonlinear de...

Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21 young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B (PiB) for amyloid-β (Aβ). The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau– OA), to high tau pathology, also occurring in temporal and limbic regions (Tau+ OA). Low le...

AMPA receptor (AMPAR) mobility within synapses has been extensively studied in vitro . However, whether similar mobility properties apply to AMPARs in vivo has yet to be determined. Here, we use two-photon-fluorescence recovery after photobleaching (FRAP) to study AMPAR mobility within individual dendritic spines in live animals using an overexpression vector. We demonstrate the existence of mobile and immobile fractions of AMPARs across multiple cortical regions and layers. Additionally, we found that AMPAR mobility can be altered in vivo in response to administration of corticosterone, a condition that mimics exposure to stress. Significance Statement Our work provides novel insight to receptor mobility within intact brains of live mice using live two-photon microscopy through cranial windows. In vivo assessment of protein mobility within mammalian neuronal synapses have thus far been limited. Here, within this system, we are able to confirm that there are both mobile and immobile AMPA receptor (AMPAR...

Loss of olfactory sensory neurons (OSNs) after injury to the olfactory epithelium (OE) triggers the generation of OSNs that are incorporated into olfactory circuits to restore olfactory sensory perception. This study addresses how insulin receptor-mediated signaling affects the functional recovery of OSNs after OE injury. Insulin levels were reduced in mice by ablating the pancreatic beta cells via streptozotocin injections. These streptozotocin-induced diabetic and control mice were then intraperitoneally injected with the olfactotoxic drug methimazole to selectively ablate OSNs. The OE of diabetic and control mice regenerated similarly until day 14 after injury. Thereafter, the OE of diabetic mice contained fewer mature and more apoptotic OSNs than control mice. Functionally, diabetic mice showed reduced electro-olfactogram responses and their olfactory bulbs had fewer c-Fos-active cells following odor stimulation, as well as performed worse in an odor-guided task compared to control mice. Insulin admini...

Everyday decision-making commonly involves assigning values to complex objects with multiple value-relevant attributes. Drawing on object recognition theories, we hypothesized two routes to multi-attribute evaluation: assessing the value of the whole object based on holistic attribute configuration or summing individual attribute-values. In two samples of healthy human male and female participants undergoing eye-tracking and fMRI while evaluating novel pseudo-objects, we found evidence for both forms of evaluation. Fixations to, and transitions between attributes differed systematically when the value of pseudo-objects was associated with individual attributes or attribute configurations. Ventromedial prefrontal cortex (vmPFC) and perirhinal cortex were engaged when configural processing was required. These results converge with our recent findings that individuals with vmPFC lesions were impaired in decisions requiring configural evaluation, but not when evaluating “the sum of the parts”. This suggests th...

Coordination of skilled movements and motor planning relies on formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that EphA7 and EfnA5 are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, EphA7 and EfnA5 forward and reverse inhibitory signals direct collateral extension such that EphA7 -positive frontal and occipital cortica...

Early postnatal experience shapes both inhibitory and excitatory networks in the hippocampus. However, the underlying circuit plasticity is unclear. Using an enriched environment (EE) paradigm during pre-weaning period in mice of either sex, we assessed the circuit plasticity of inhibitory cell-types in the hippocampus. We found that cholecystokinin (CCK)-expressing basket cells strongly increased somatic inhibition on the excitatory granular cells (GC) following EE, while another pivotal inhibitory cell-type, parvalbumin (PV)-expressing cells did not show changes. Using electrophysiological analysis and the use of cannabinoid receptor 1 (CB1R) agonist WIN 55,212-2, we demonstrate that the change in somatic inhibition from CCK+ neurons increases CB1R-mediated inhibition in the circuit. By inhibiting activity of the entorhinal cortex (EC) using a chemogenetic approach, we further demonstrate that the activity of the projections from the EC mediates the developmental assembly of CCK+ basket cell network. Alt...

Quantitative estimations of spatiotemporal complexity of cortical activity patterns are used in the clinic as a measure of consciousness levels, but the cortical mechanisms involved are not fully understood. We used a version of the Perturbational Complexity Index adapted to multisite recordings from the ferret (either sex) cerebral cortex in vitro (sPCI) to investigate the role of GABAergic inhibition in cortical complexity. We studied two dynamical states: slow-wave activity (synchronous state) and desynchronized activity, that express low and high causal complexity respectively. Progressive blockade of GABAergic inhibition during both regimes revealed its impact on the emergent cortical activity and on sPCI. Gradual GABAA receptor blockade resulted in higher synchronization, being able to drive the network from a desynchronized to a synchronous state, with a progressive decrease of complexity (sPCI). Blocking GABAB receptors also resulted in a reduced sPCI, in particular when in a synchronous, slow wave...

Glutamatergic input via NMDA and AMPA receptors within the mesolimbic dopamine pathway plays a critical role in the development of addictive behavior and relapse towards drugs of abuse. Although well-established for drugs of abuse, it is not clear whether glutamate receptors within the mesolimbic system are involved in mediating chronic consumption and relapse following abstinence from a non-drug reward. Here we evaluated the contribution of mesolimbic glutamate receptors in mediating chronic sugar consumption and the sugar deprivation effect (SDE), which is used as a measure of relapse-like behavior following abstinence. We studied four inducible mutant mouse lines lacking the GluA1 or GluN1 subunit in either dopamine transporter (DAT) or D1R-expressing neurons in an automated monitoring system for free-choice sugar drinking in the home cage. Mice lacking either GluA1 or GluN1 in D1R expressing neurons ( GluA1D1CreERT2 or GluN1D1CreERT2 mice) have altered sugar consumption in both sexes, whereas GluA1DATC...