No abstract

Inhibitory interneurons sculpt the outputs of excitatory circuits to expand the dynamic range of information processing. In mammalian retina, >30 types of amacrine cells provide lateral inhibition to vertical, excitatory bipolar cell circuits, but functional roles for only a few amacrine cells are well established. Here, we elucidate the function of corticotropin-releasing hormone (CRH)-expressing amacrine cells labeled in Cre-transgenic mice of either sex. CRH cells costratify with the ON alpha ganglion cell, a neuron highly sensitive to positive contrast. Electrophysiological and optogenetic analyses demonstrate that two CRH types (CRH-1 and CRH-3) make GABAergic synapses with ON alpha cells. CRH-1 cells signal via graded membrane potential changes, whereas CRH-3 cells fire action potentials. Both types show sustained ON-type responses to positive contrast over a range of stimulus conditions. Optogenetic control of transmission at CRH-1 synapses demonstrates that these synapses are tuned to low temporal frequencies, maintaining GABA release during fast hyperpolarizations during brief periods of negative contrast. CRH amacrine cell output is suppressed by prolonged negative contrast, when ON alpha ganglion cells continue to receive inhibitory input from converging OFF-pathway amacrine cells; the converging ON- and OFF-pathway inhibition balances tonic excitatory drive to ON alpha cells. Previously, it was demonstrated that CRH-1 cells inhibit firing by suppressed-by-contrast (SbC) ganglion cells during positive contrast. Therefore, divergent outputs of CRH-1 cells inhibit two ganglion cell types with opposite responses to positive contrast. The opposing responses of ON alpha and SbC ganglion cells are explained by differing excitation/inhibition balance in the two circuits. A goal of neuroscience research is to explain the function of neural circuits at the level of specific cell types. Here, we studied the function of specific types of inhibitory interneurons, corticotropin-releasing hormone (CRH) amacrine cells, in the mouse retina. Genetic tools were used to identify and manipulate CRH cells, which make GABAergic synapses with a well studied ganglion cell type, the ON alpha cell. CRH cells converge with other types of amacrine cells to tonically inhibit ON alpha cells and balance their high level of excitation. CRH cells diverge to different types of ganglion cell, the unique properties of which depend on their balance of excitation and inhibition.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) exhibit melanopsin-dependent light responses that persist in the absence of rod and cone photoreceptor-mediated input. In addition to signaling anterogradely to the brain, ipRGCs signal retrogradely to intraretinal circuitry via gap junction-mediated electrical synapses with amacrine cells (ACs). However, the targets and functions of these intraretinal signals remain largely unknown. Here, in mice of both sexes, we identify circuitry that enables M5 ipRGCs to locally inhibit retinal neurons via electrical synapses with a nonspiking GABAergic AC. During pharmacological blockade of rod-and cone-mediated input, whole-cell recordings of corticotropin-releasing hormone-expressing (CRH 1 ) ACs reveal persistent visual responses that require both melanopsin expression and gap junctions. In the developing retina, ipRGC-mediated input to CRH 1 ACs is weak or absent before eye opening, indicating a primary role for this input in the mature retina (i.e., in parallel with rod-and cone-mediated input). Among several ipRGC types, only M5 ipRGCs exhibit consistent anatomical and physiological coupling to CRH 1 ACs. Optogenetic stimulation of local CRH 1 ACs directly drives IPSCs in M4 and M5, but not M1-M3, ipRGCs. CRH 1 ACs also inhibit M2 ipRGC-coupled spiking ACs, demonstrating direct interaction between discrete networks of ipRGC-coupled interneurons. Together, these results demonstrate a functional role for electrical synapses in translating ipRGC activity into feedforward and feedback inhibition of local retinal circuits.

Night vision in mammals depends fundamentally on rod photoreceptors and the well-studied rod bipolar (RB) cell pathway. The central neuron in this pathway, the AII amacrine cell (AC), exhibits a spatially tuned receptive field, composed of an excitatory center and an inhibitory surround, that propagates to ganglion cells, the retina’s projection neurons. The circuitry underlying the surround of the AII, however, remains unresolved. Here, we combined structural, functional and optogenetic analyses of the mouse retina to discover that surround inhibition of the AII depends primarily on a single interneuron type, the NOS-1 AC: a multistratified, axon-bearing GABAergic cell, with dendrites in both ON and OFF synaptic layers, but with a pure ON (depolarizing) response to light. Our study demonstrates generally that novel neural circuits can be identified from targeted connectomic analyses and specifically that the NOS-1 AC mediates long-range inhibition during night vision and is a major element of the RB pathway.

Pairing a conditioned stimulus (CS) with ethanol generally produces aversion for that CS in adult rodents. However, infant rats (PD1-PD3) exposed to ethanol demonstrate appetitive reinforcement to ethanol (Petrov et al., 2003; Nizhnikov et al., 2006a). This sensitivity to the appetitive properties of ethanol during infancy may be transient, as during the second postnatal week rat pups tend to exhibit conditioned aversions to flavors paired with ethanol. The present study examined changes in the motivation properties of ethanol through ontogeny and the neurobiology underlying these changes. Rat pups were exposed to a taste conditioning procedure on PD4 or PD12. Rat pups were intraorally infused with 2.5% of their body weight of saccharin solution (0.1%) and immediately after injected intraperitoneolly (i.p.) with one of six doses of ethanol (0.0–2.0 g/kg). A day later pups were given saccharine infusions and percent body weight gain was used as an index of ethanol’s reinforcing effects. PD4 pups expressed appetitive reinforcement to ethanol, as indicated by greater saccharin intake, as compared to control counterparts and to the older PD12 pups. Subsequent experiments revealed that PD4 pups were less sensitive to the aversive properties of the drug than PD12 pups. The older pups found high doses of ethanol aversive while PD4 rat pups did not condition aversions to this dose of ethanol after a single trial. A similar pattern of results was observed between the low doses of ethanol and the highest doses of a kappa opioid agonist. The PD12 animals did not condition to the kappa opioid agonist, while the younger rats expressed an appetitive response. These results illustrate an ontogenetic change in the motivational properties of ethanol, with sensitivity to its appetitive properties declining and responsiveness to the aversive properties increasing with age during early infancy.