Plasticity of local GABAergic interneurons drives olfactory habituation

Abstract

Despite its ubiquity and significance, behavioral habituation is poorly understood in terms of the underlying neural circuit mechanisms. Here, we present evidence that habituation arises from potentiation of inhibitory transmission within a circuit motif commonly repeated in the nervous system. In Drosophila, prior odorant exposure results in a selective reduction of response to this odorant. Both short-term (STH) and long-term (LTH) forms of olfactory habituation require function of the rutabaga-encoded adenylate cyclase in multiglomerular local interneurons (LNs) that mediate GABAergic inhibition in the antennal lobe; LTH additionally requires function of the cAMP response element-binding protein (CREB2) transcription factor in LNs. The odorant selectivity of STH and LTH is mirrored by requirement for NMDA receptors and GABA A receptors in odorant-selective, glomerulus-specific projection neurons (PNs). The need for the vesicular glutamate transporter in LNs indicates that a subset of these GABAergic neurons also releases glutamate. LTH is associated with a reduction of odorant-evoked calcium fluxes in PNs as well as growth of the respective odorant-responsive glomeruli. These cellular changes use similar mechanisms to those required for behavioral habituation. Taken together with the observation that enhancement of GABAergic transmission is sufficient to attenuate olfactory behavior, these data indicate that habituation arises from glomerulus-selective potentiation of inhibitory synapses in the antennal lobe. We suggest that similar circuit mechanisms may operate in other species and sensory systems.abituation is a specific form of implicit learning in which repeated exposure to an unreinforced stimulus results in a decreased behavioral response (1-3). By filtering out such constant sensory input, habituation enhances an animal's ability to focus its cognitive resources on novel or salient features of the environment. Thus, habituation serves as a building block for normal cognition (2, 4). Although it has been studied in many different contexts, causal connections between mechanisms, neuronal changes, and behavioral habituation have not been clearly identified (2). Given our current understanding, it remains unclear whether similar or distinct mechanisms underlie different forms of habituation; also unclear is how these mechanisms compare with those mechanisms used in consolidation or extinction of associative memory (1, 5).The olfactory system provides an experimentally accessible circuit in which to analyze mechanisms that underlie different timescales of behavioral habituation (4, 6, 7). Particularly useful is the adult Drosophila olfactory system, which has organization similar to that of mammals (8, 9). Here, olfactory sensory neurons (OSNs) expressing a single type of functional odorant receptor molecules (ORs) send axons to the antennal lobe and synapse onto (i) glomerulus-specific projection neurons (PNs) that project to the mushroom body and lateral horn, (ii) multiglomerular local interneurons (LNs...

FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control

“…As expected, the same flies show normal LTH to CO 2 ( Fig. 2 E and F), because GH146-Gal4 marks PNs that innervate EB-responsive glomeruli but not those that innervate the (46). (B) Flies were exposed to EB (black bars) or CO 2 (gray bars) for 30 min or not exposed to any odor (white bars).…”

“…CO 2 -responsive V glomerulus (46,51). Thus, dFmr1 is required in adult PNs to mediate odorant-selective LTH.…”

“…The shared association of dFmr1 and Atx2 with stress granules and miRNA function led us to ask whether dFmr1 was required like Atx2 for LTH but not short-term habituation (STH). This issue is of interest because the simple and genetically accessible circuitry involved in olfactory habituation would allow us to compare the cell type-specific requirements for both proteins (31,46).…”

“…EB LTH is associated with a reduction in the EB-evoked physiological response of the DM5 PN, measured using functional imaging of odor-evoked responses through PN-expressed GCaMP, a genetically encoded calcium sensor that reports calcium fluxes in vivo (31,46,52). We tested whether this LTHassociated form of neural plasticity was dependent on dFmr1 function in PNs.…”

“…Here, a simple Atx2-dependent form of long-term memory, long-term habituation (LTH), arises from the plasticity of inhibitory transmission between two cell types, local circuit interneurons (LNs) and output projection neurons (PNs) (31,46,47). This potentially allows us to ask whether dFmr1 and Atx2 function in the same cells for LTH formation.…”