To assemble the functional circuits of the nervous system, the neuronal axonal growth cones must be precisely guided to their proper targets, which can be achieved through cell–surface guidance receptor activation by ligand binding in the periphery. We investigated the function of paxillin, a focal adhesion protein, as an essential growth cone guidance intermediary in the context of spinal lateral motor column (LMC) motor axon trajectory selection in the limb mesenchyme. Using in situ mRNA detection, we first show paxillin expression in LMC neurons of chick and mouse embryos at the time of spinal motor axon extension into the limb. Paxillin loss-of-function and gain-of-function using in ovo electroporation in chick LMC neurons, of either sex, perturbed LMC axon trajectory selection, demonstrating an essential role of paxillin in motor axon guidance. In addition, a neuron-specific paxillin deletion in mice led to LMC axon trajectory selection errors. We also show that knocking down paxillin attenuates the g...

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...

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...

Humans have large social networks, with hundreds of interacting individuals. How does the brain represent the complex connectivity structure of these networks? Here we used social media (Facebook) data to objectively map participants’ real-life social networks. We then used representational similarity analysis (RSA) of fMRI activity patterns to investigate the neural coding of these social networks as participants reflected on each individual. We found coding of social network distances in the default-mode network (medial prefrontal, medial parietal and lateral parietal cortices). When using partial correlation RSA to control for other factors that can be correlated to social distance (personal affiliation, personality traits and visual appearance, as subjectively rated by the participants), we found that social network distance information was uniquely coded in the retrosplenial complex, a region involved in spatial processing. In contrast, information on individuals’ personal affiliation to the participa...