Distinct neural circuits establish the same chemosensory behavior in C. elegans

Animals frequently exhibit the same behavior under different environmental or physiological conditions. To what extent these behaviors are generated by similar vs. distinct mechanisms is unclear. Moreover, the circumstances under which divergent neural mechanisms establish the same behavior, and the molecular signals that regulate the same behavior across conditions, are poorly understood. We show that in C. elegans, distinct neural mechanisms mediate the same chemosensory behavior at two different life stages. Both dauer larvae and starved adults are attracted to carbon dioxide (CO2), but CO2 attraction is mediated by distinct sets of interneurons at the two life stages. Some interneurons mediate CO2 response only in dauers, some show CO2-evoked activity in adults and dauers but contribute to CO2 response only in adults, and some show CO2-evoked activity that opposes CO2 attraction in adults but promotes CO2 attraction in dauers. We also identify a novel role for insulin signaling in establishing life-stage-specific CO2 responses by modulating interneuron activity. Further, we show that a combinatorial code of both shared and life-stage-specific molecular signals regulate CO2 attraction. Our results identify a mechanism by which the same chemosensory behavior can be generated by distinct neural circuits, revealing an unexpected complexity to chemosensory processing.

The diagonal band of broca continually regulates olfactory-mediated behaviors by modulating odor-evoked responses within the olfactory bulb

Sensory perception is modulated in a top-down fashion by higher brain regions to regulate the strength of its own input resulting in the adaptation of behavioral responses. In olfactory perception, the horizontal diagonal band of broca (HDB), embedded in the basal forebrain modulates olfactory information processing by recruiting olfactory bulb (OB) interneuron activity to shape excitatory OB output. Currently, little is known about how specific HDB to OB top down signaling affects complex olfactory-mediated behaviors. Here we show that the olfactory bulb is strongly and differentially innervated by HDB projections. HDB-silencing via tetanus toxin lead to reduced odor-evoked Ca2+-responses in glomeruli of the main OB, underscoring the HDB’s role in odor response modulation. Furthermore, selective, light-mediated silencing of only HDB to OB afferents completely prevented olfactory-mediated habituation and discrimination behaviors. Notably, also social habituation and discrimination behaviors were affected. Here we provide evidence for a novel tri-synaptic paraventricular nucleus (PVN)-HDB-OB axis responsible for modulating these types of behavior. Thus, HDB to OB projections constitute a central top-down pathway for olfactory-mediated habituation and discrimination.

Hippocampal dentate gyrus coordinates brain-wide communication and memory updating through an inhibitory gating

Distinct forms of memory processing are often causally identified with specific brain regions, but a key facet of memory processing includes linking separated neuronal populations. Using cell-specific manipulations of inhibitory neuronal activity, we discovered a key role of the dentate gyrus (DG) in coordinating dispersed neuronal populations during memory formation. In whole-brain fMRI and electrophysiological experiments, we found that parvalbumin (PV) interneurons in the DG control the functional coupling of the hippocampus within a wider network of neocortical and subcortical structures including the prefrontal cortex (PFC) and the nucleus accumbens (NAc). In a novel object-location task, regulation of PV interneuron activity enhanced or prevented memory encoding and, without effect upon the total number of task activated c-Fos+ cells, revealed a correlation between activated neuronal populations in the hippocampus-PFC-NAc network. These data suggest a critical regulatory role of PV interneurons in the dentate gyrus in brain-wide polysynaptic communication channels and the association of cell assemblies across multiple brain regions.

Contrast gain control occurs independently of both parvalbumin-positive interneuron activity and shunting inhibition in auditory cortex

We investigated whether contrast gain control is mediated by shunting inhibition from parvalbumin-positive interneurons in auditory cortex. We performed extracellular and intracellular recordings in mouse auditory cortex while presenting sensory stimuli with varying contrasts and manipulated parvalbumin-positive interneuron activity using optogenetics. We show that while parvalbumin-positive interneuron activity modulates the gain of cortical responses, this activity is not the primary mechanism for contrast gain control in auditory cortex.

Shifting hippocampal excitation/inhibition balance modifies despair-like behavior in mice

Despair is a core symptom of depressive disorders. However, little is known about the neural circuits mediating despair and how they are modified by antidepressants. Here we show that the balance between excitatory and inhibitory neurotransmission (E/I balance) in the hippocampus affects behavioral despair in mice. Reduced interneuron density, knockdown of Gabrg2 or DREADD-mediated suppression of interneuron activity resulted in disinhibition of CA1 neurons and anti-despair-like behaviors in mice. Conversely, pharmacological and chemogenetic potentiation of GABAergic transmission in CA1 neurons rapidly induced despair-like behaviors. Disinhibition induced by the GABAAR antagonist pentylenetetrazol produced transient antidepressant effects without BDNF elevation in the hippocampus, while ketamine exhibited rapid and sustained antidepressant effects, but the latter was sensitive to the TrkB receptor blocker ANA-12. These results suggest that rapid disinhibition and BDNF-induced long-lasting synaptic modification leads to enhanced E/I balance, which may contribute to acute and sustained behavioral effects of rapid-acting antidepressants.