In the midbrain ventral tegmental area (VTA), both dopaminergic and nondopaminergic neural substrates mediate various behavioural reward phenomena. VTA GABAergic neurons are anatomically positioned to influence the activity of both the mesolimbic dopamine system and nondopamine efferents from the VTA. In order to examine the possible functional role of VTA GABA(A) receptors in neural reward processes, we performed discrete, bilateral microinjections of the GABA(A) receptor agonist, muscimol, or the GABA(A) receptor antagonist, bicuculline, into the VTA. Using a fully counterbalanced, unbiased conditioned place-preference paradigm, we demonstrate that activation of VTA GABA(A) receptors, with the GABA(A) receptor agonist muscimol (5--50 ng/microL), or inhibition of VTA GABA(A) receptors, with the GABA(A) receptor antagonist bicuculline (5--50 ng/microL), both produce robust rewarding effects. Furthermore, these rewarding effects can be pharmacologically dissociated: blockade of dopamine receptors with a dopamine receptor antagonist, alpha-flupenthixol (0.8 mg/kg; i.p.), or concurrent activation of VTA GABA(B) receptors with a GABA(B) receptor agonist, baclofen (70 ng/microL), blocked the rewarding properties of the GABA(A) receptor agonist, but had no effect on the rewarding properties of the GABA(A) receptor antagonist. These results suggest that, within the VTA, a single GABA(A) receptor substrate controls bidirectional reward signalling between dopaminergic and nondopaminergic brain reward systems.

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Unilateral lesions of the substantia nigra in the first postnatal week cause a massive shrinkage (> 50%) of the ipsilateral rat striatum, due primarily to neuronal cell death. Striatal patch neurons (marked by retrograde labeling from the substantia nigra prior to the lesions) selectively survive the striatal cell death caused by the lesions. However, after the lesions these early retrogradely labeled patch neurons are distributed diffusely through the remaining striatum, in contrast to their normal patchy distribution throughout the postnatal period. Thus, many striatal neurons (but not the patch and matrix neurons with early axonal projections to the substantia nigra) are critically dependent upon interactions with the substantia nigra for their survival during the early postnatal period, and in the absence of these missing striatal and substantia nigra neurons, the remaining striatal patch neurons are no longer distributed in a patchy fashion.

The molecules and mechanisms that are involved in the acquisition, storage, and retrieval of memories in many organisms are unclear. To investigate these processes, we use the nematode worm Caenorhabditis elegans, which is attracted naïvely to the odorant benzaldehyde but learns to avoid it after paired exposure with starvation. Mutations in the receptor‐like guanylate cyclase GCY‐28 have previously been thought to result in a behavioral switch in the primary chemosensory neuron AWCON, from an attractive state to an aversive (already‐learned) state. Here, we offer a different interpretation and show that GCY‐28 functions in distinct neurons to modulate two independent processes: naïve attraction to AWCON‐sensed odors in the AWCON neuron, and associative learning of benzaldehyde and starvation in the AIA interneurons. Consequently, mutants that lack gcy‐28 do not approach AWCON‐sensed odors and cannot associate benzaldehyde with starvation. We further show that this learning deficit lies in memory retrieval, not in its acquisition or storage, and that GCY‐28 is required in AIA for sensory integration only when both AWC neurons (ON and OFF) are activated by chemical stimuli. Our results reveal a novel role of GCY‐28 in the retrieval of associative memories and may have wide implications for the neural machineries of learning and memory in general.