Photopharmacology is a unique approach that through a combination of photochemistry methods and advanced life science techniques allows the study and control of specific biological processes, ranging from intracellular pathways to brain circuits. Recently, a first photochromic channel blocker of anion-selective GABAA receptors, the azobenzene-nitrazepam-based photochromic compound (Azo-NZ1), has been described. In the present study, using patch-clamp technique in heterologous system and in mice brain slices, site-directed mutagenesis and molecular modeling we provide evidence of the interaction of Azo-NZ1 with glycine receptors (GlyRs) and determine the molecular basis of this interaction. Glycinergic synaptic neurotransmission determines an important inhibitory drive in the vertebrate nervous system and plays a crucial role in the control of neuronal circuits in the spinal cord and brain stem. GlyRs are involved in locomotion, pain sensation, breathing, and auditory function, as well as in the development...

For decades, a role for the Ca2+-binding protein calmodulin (CaM) in Ca2+-dependent presynaptic modulation of synaptic transmission has been recognized. Here, we investigated the influence of CaM on evoked and spontaneous neurotransmission at rod bipolar (RB) cell→AII amacrine cell synapses in the mouse retina. Our work was motivated by the observations that expression of CaM in RB axon terminals is extremely high and that [Ca2+] in RB terminals normally rises sufficiently to saturate endogenous buffers, making tonic CaM activation likely. Taking advantage of a model in which RBs can be stimulated by expressed channelrhodopsin-2 (ChR2) to avoid dialysis of the presynaptic terminal, we found that inhibition of CaM dramatically decreased evoked release by inhibition of presynaptic Ca channels while at the same time potentiating both Ca2+-dependent and Ca2+-independent spontaneous release. Remarkably, inhibition of myosin light chain kinase (MLCK), but not other CaM-dependent targets, mimicked the effects of ...

Speech signals have a unique shape of long-term modulation spectrum that is distinct from environmental noise, music, and non-speech vocalizations. Does the human auditory system adapt to the speech long-term modulation spectrum and efficiently extract critical information from speech signals? To answer this question, we tested whether neural responses to speech signals can be captured by specific modulation spectra of non-speech acoustic stimuli. We generated amplitude modulated (AM) noise with the speech modulation spectrum and 1/f modulation spectra of different exponents to imitate temporal dynamics of different natural sounds. We presented these AM stimuli and a 10-min piece of natural speech to 19 human participants undergoing electroencephalography (EEG) recording. We derived temporal response functions (TRFs) to the AM stimuli of different spectrum shapes and found distinct neural dynamics for each type of TRFs. We then used the TRFs of AM stimuli to predict neural responses to the speech signals, ...

A key aspect of behavioral inhibition is the ability to wait before acting. Failures in this form of inhibition result in impulsivity and are commonly observed in various neuropsychiatric disorders. Prior evidence has implicated medial frontal cortex, motor cortex, orbitofrontal cortex (OFC), and ventral striatum in various aspects of inhibition. Here, using distributed recordings of brain activity [with local-field potentials (LFPs)] in rodents, we identified oscillatory patterns of activity linked with action and inhibition. Low-frequency (δ) activity within motor and premotor circuits was observed in two distinct networks, the first involved in cued, sensory-based responses and the second more generally in both cued and delayed actions. By contrast, θ activity within prefrontal and premotor regions (medial frontal cortex, OFC, ventral striatum, and premotor cortex) was linked with inhibition. Connectivity at θ frequencies was observed within this network of brain regions. Interestingly, greater connecti...

The WU-Minn Human Connectome Project (HCP) is a publicly-available dataset containing state-of-the-art structural magnetic resonance imaging (MRI), functional MRI (fMRI), and diffusion MRI (dMRI) for over a thousand healthy subjects. While the planned scope of the HCP included an anatomic connectome, resting-state fMRI (rs-fMRI) forms the bulk of the HCP’s current connectomic output. We address this by presenting a full-cortex connectome derived from probabilistic diffusion tractography and organized into the HCP-MMP1.0 atlas. Probabilistic methods and large sample sizes are preferable for whole-connectome mapping as they increase the fidelity of traced low-probability connections. We find that overall, connection strengths are lognormally distributed and decay exponentially with tract length, that connectivity reasonably matches macaque histologic tracing in homologous areas, that contralateral homologs and left-lateralized language areas are hyperconnected, and that hierarchical similarity influences con...

Several neurodevelopmental disabilities are strongly associated with alterations in GABAergic transmission, and therapies to stimulate its normal development are lacking. Erythropoietin (EPO) is clinically used in neonatology to mitigate acute brain injury, and to stimulate neuronal maturation. Yet it remains unclear whether EPO can stimulate maturation of the GABAergic system. Here, with the use of a transgenic mouse line that constitutively overexpresses neuronal EPO (Tg21), we show that EPO stimulates postnatal GABAergic maturation in the hippocampus. We show an increase in hippocampal GABA-immunoreactive neurons, and postnatal elevation of interneurons expressing parvalbumin (PV), somatostatin (SST), and neuropeptide Y (NPY). Analysis of perineuronal net (PNN) formation and innervation of glutamatergic terminals onto PV+ cells, shows to be enhanced early in postnatal development. Additionally, an increase in GABAAergic synapse density and IPSCs in CA1 pyramidal cells from Tg21 mice is observed. Detecti...

The medial entorhinal cortex (mEC) shows a high degree of spatial tuning, predominantly grid cell activity, which is reliant on robust, dynamic inhibition provided by local interneurons (INs). In fact, feedback inhibitory microcircuits involving fast-spiking parvalbumin (PV) basket cells (BCs) are believed to contribute dominantly to the emergence of grid cell firing in principal cells (PrCs). However, the strength of PV BC-mediated inhibition onto PrCs is not uniform in this region, but high in the dorsal and weak in the ventral mEC. This is in good correlation with divergent grid field sizes, but the underlying morphologic and physiological mechanisms remain unknown. In this study, we examined PV BCs in layer (L)2/3 of the mEC characterizing their intrinsic physiology, morphology and synaptic connectivity in the juvenile rat. We show that while intrinsic physiology and morphology are broadly similar over the dorsoventral axis, PV BCs form more connections onto local PrCs in the dorsal mEC, independent of...

Polychlorinated biphenyls (PCBs) are enduring environmental toxicants and exposure is associated with neurodevelopmental deficits. The auditory system appears particularly sensitive, as previous work has shown that developmental PCB exposure causes both hearing loss and gross disruptions in the organization of the rat auditory cortex. However, the mechanisms underlying PCB-induced changes are not known, nor is it known whether the central effects of PCBs are a consequence of peripheral hearing loss. Here, we study changes in both peripheral and central auditory function in rats with developmental PCB exposure using a combination of optical and electrophysiological approaches. Female rats were exposed to an environmental PCB mixture in utero and until weaning. At adulthood, auditory brainstem responses (ABRs) were measured, and synaptic currents were recorded in slices from auditory cortex layer 2/3 neurons. Spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) were more frequent in PCB-exposed rats compa...

The regulation of neuronal soma size is essential for appropriate brain circuit function and its dysregulation is associated with several neurodevelopmental disorders. A defect in the dendritic growth and elaboration of motor neocortical pyramidal neurons in neonates lacking neuregulin-4 (NRG4) has previously been reported. In this study, we investigated whether the loss of NRG4 causes further morphologic defects that are specific to these neurons. We analyzed the soma size of pyramidal neurons of layer (L)2/3 and L5 of the motor cortex and a subpopulation of multipolar interneurons in this neocortical region in Nrg4 +/+ and Nrg4 −/− mice. There were significant decreases in pyramidal neuron soma size in Nrg4 −/− mice compared with Nrg4 +/+ littermates at all stages studied [postnatal day (P)10, P30, and P60]. The reduction was especially marked at P10 and in L5 pyramidal neurons. Soma size was not significantly different for multipolar interneurons at any age. This in vivo phenotype was replicated in pyra...

Neurophysiology studies require the use of inclusion criteria to identify neurons responsive to the experimental stimuli. Five recent studies used calcium imaging to measure the preferred tuning properties of layer 2/3 pyramidal neurons in mouse visual areas. These five studies employed different inclusion criteria and reported different, sometimes conflicting results. Here, we examine how different inclusion criteria can impact reported tuning properties, modifying inclusion criteria to select different subpopulations from the same dataset of almost 17,000 layer 2/3 neurons from the Allen Brain Observatory. The choice of inclusion criteria greatly affected the mean tuning properties of the resulting subpopulations; indeed, the differences in mean tuning because of inclusion criteria were often of comparable magnitude to the differences between studies. In particular, the mean preferred temporal frequencies (TFs) of visual areas changed markedly with inclusion criteria, such that the rank ordering of visua...