Neural dynamics underlying associative learning in the dorsal and ventral hippocampus.

Animals associate cues with outcomes and update these associations as new information is presented. This requires the hippocampus, yet how hippocampal neurons track changes in cue-outcome associations remains unclear. Using two-photon calcium imaging, we tracked the same dCA1 and vCA1 neurons across days to determine how responses evolve across phases of odor-outcome learning. Initially, odors elicited robust responses in dCA1, whereas, in vCA1, odor responses primarily emerged after learning and embedded information about the paired outcome. Population activity in both regions rapidly reorganized with learning and then stabilized, storing learned odor representations for days, even after extinction or pairing with a different outcome. Additionally, we found stable, robust signals across CA1 when mice anticipated outcomes under behavioral control but not when mice anticipated an inescapable aversive outcome. These results show how the hippocampus encodes, stores and updates learned associations and illuminates the unique contributions of dorsal and ventral hippocampus.

Substrate recognition and proton coupling by a bacterial member of solute carrier family 17.

The solute carrier 17 family transports diverse organic anions using two distinct modes of coupling to a source of energy. Transporters that package glutamate and nucleotide into secretory vesicles for regulated release by exocytosis are driven by membrane potential but subject to allosteric regulation by H+ and Cl-. Other solute carrier 17 members including the lysosomal sialic acid exporter couple the flux of organic anion to cotransport of H+. To begin to understand how similar proteins can perform such different functions, we have studied Escherichia coli DgoT, a H+/galactonate cotransporter. A recent structure of DgoT showed many residues contacting D-galactonate, and we now find that they do not tolerate even conservative substitutions. In contrast, the closely related lysosomal H+/sialic acid cotransporter Sialin tolerates similar mutations, consistent with its recognition of diverse substrates with relatively low affinity. We also find that despite coupling to H+, DgoT transports more rapidly but with lower apparent affinity at high pH. Indeed, membrane potential can drive uptake, indicating electrogenic transport and suggesting a H+:galactonate stoichiometry >1. Located in a polar pocket of the N-terminal helical bundle, Asp46 and Glu133 are each required for net flux by DgoT, but the E133Q mutant exhibits robust exchange activity and rescues exchange by D46N, suggesting that these two residues operate in series to translocate protons. E133Q also shifts the pH sensitivity of exchange by DgoT, supporting a central role for the highly conserved TM4 glutamate in H+ coupling by DgoT.

Activation, but not inhibition, of the indirect pathway disrupts choice rejection in a freely moving, multiple-choice foraging task.

The dorsomedial striatum (DMS) plays a key role in action selection, but less is known about how direct and indirect pathway spiny projection neurons (dSPNs and iSPNs, respectively) contribute to choice rejection in freely moving animals. Here, we use pathway-specific chemogenetic manipulation during a serial choice foraging task to test the role of dSPNs and iSPNs in learned choice rejection. We find that chemogenetic activation, but not inhibition, of iSPNs disrupts rejection of nonrewarded choices, contrary to predictions of a simple "select/suppress" heuristic. Our findings suggest that iSPNs' role in stopping and freezing does not extend in a simple fashion to choice rejection in an ethological, freely moving context. These data may provide insights critical for the successful design of interventions for addiction or other conditions in which it is desirable to strengthen choice rejection.