The hippocampus is essential for representing spatiotemporal context and associating it with the sensory details of daily life to form episodic memories. However, the neural circuit underlying this process remains poorly understood. We selectively inhibited hippocampal projections to the anterior olfactory nucleus (AON) during behavioural tests of contextually-cued odour recall. We found that inhibition of intermediate HPC (iHPC)-lateral AON (lAON) pathway impaired spatial odour memory while inhibition of ventral HPC (vHPC)-medial AON (mAON) pathway disrupted both spatial and temporal odour memory. Our results indicate that the spatial and temporal information of episodic-like odour memory is conveyed by topographically distinct hippocampal-AON pathways.
Highlights•The vHPC-NAc circuit encodes contexts associated with food reward•vHPC cholecystokinin (CCK) interneurons inhibit vCA1→NAc projecting pyramidal cells•Silencing CCK interneurons in a reward context increased activity of vCA1→NAc cells•Silencing CCK interneurons improved the encoding of contextual reward memorySummaryAssociating contexts with rewards depends on hippocampal circuits, with local inhibitory interneurons positioned to play an important role in shaping activity. Here, we demonstrate that the encoding of context-reward memory requires a ventral hippocampus (vHPC) to nucleus accumbens (NAc) circuit that is gated by cholecystokinin (CCK) interneurons. In a sucrose conditioned place preference (CPP) task, optogenetically inhibiting vHPC-NAc terminals impaired the acquisition of place preference. Transsynaptic rabies tracing revealed vHPC-NAc neurons were monosynaptically innervated by CCK interneurons. Using intersectional genetic targeting of CCK interneurons, ex vivo optogenetic activation of CCK interneurons increased GABAergic transmission onto vHPC-NAc neurons, while in vivo optogenetic inhibition of CCK interneurons increased cFos in these projection neurons. Notably, CCK interneuron inhibition during sucrose CPP learning increased time spent in the sucrose-associated location, suggesting enhanced place-reward memory. Our findings reveal a previously unknown hippocampal microcircuit crucial for modulating the strength of contextual reward learning.Graphical abstract
Hippocampal input to the hypothalamus is known to be critically involved in mediating the negative feedback inhibition of stress response. However, the underlying neural circuitry has not been fully elucidated. Using a combination of rabies tracing, pathway-specific optogenetic inhibition, and cell-type specific synaptic silencing, the present study examined the role of hippocampal input to the hypothalamus in modulating neuroendocrine and behavioral responses to stress in mice. Transsynaptic rabies tracing revealed that the ventral hippocampus (vHPC) is monosynaptically connected to inhibitory cells in the anterior hypothalamic nucleus (AHN-GABA cells). Optogenetic inhibition of the vHPC→AHN pathway during a restraint stress resulted in a prolonged and exaggerated release of corticosterone, accompanied by an increase in stress-induced anxiety behaviors. Consistently, tetanus toxin-mediated synaptic inhibition in AHN-GABA cells produced a remarkably similar effect on the corticosterone release profile, corroborating the role of HPC→AHN pathway in mediating the hippocampal control of stress responses. Lastly, we found that chronic inhibition of AHN-GABA cells leads to cognitive impairments in both object and social recognition memory. Together, our data present a novel hypothalamic circuit for the modulation of adaptive stress responses, the dysfunction of which has been implicated in various affective disorders.
Innate defensive behaviors, such as freezing, fleeing, and fighting, are essential for survival, enabling animals to effectively respond to predatory threats. These behaviors involve a complex interplay of sensory processing, decision-making, and motor output. As a core component of the medial hypothalamic defense system, the anterior hypothalamic nucleus (AHN) is a key brain region implicated in orchestrating innate defensive responses. Although the AHN is predominantly GABAergic, it also contains a smaller population of excitatory neurons, reflecting a sophisticated balance between inhibitory and excitatory signaling within this region. However, despite its importance, the specific behavioral functions of these diverse neuronal populations have not been systemically examined. In this study, we utilized fiber photometry and optogenetic stimulation to investigate the roles of AHN GABAergic, glutamatergic, and CaMKIIa+ neuronal activities in mediating innate defensive behaviors. Our results indicate that AHN GABAergic neurons mediate anxiety-associated investigatory behaviors, likely facilitating risk assessment during the pre-encounter stage. Conversely, AHN glutamatergic neurons drive escape initiation and freezing responses associated with the post-encounter stage. The AHN CaMKIIa+ neurons, which exhibit significant heterogeneity, suggest a more nuanced role, potentially balancing escape and freezing responses. By elucidating the functional specialization of different AHN neuron subtypes, this study provides a foundation for future investigations into the neural circuits underlying innate defensive behaviors and its dysregulation in neuropsychiatric conditions characterized by dysregulated responses to threats, such as PTSD and panic disorder.
Opioids induce rewarding and locomotor effects by inhibiting rostromedial tegmental GABA neurons that express μ-opioid and nociceptin receptors. These GABA neurons then strongly inhibit dopamine neurons. Opioid-induced reward, locomotion and dopamine release also depend on pedunculopontine and laterodorsal tegmental cholinergic and glutamate neurons, many of which project to and activate ventral tegmental area dopamine neurons. Here we show that laterodorsal tegmental and pedunculopontine cholinergic neurons project to both rostromedial tegmental nucleus and ventral tegmental area, and that M4 muscarinic receptors are co-localized with μ-opioid receptors associated with rostromedial tegmental GABA neurons. To inhibit or excite rostromedial tegmental GABA neurons, we utilized adeno-associated viral vectors and DREADDs to express designed muscarinic receptors (M4D or M3D respectively) in GAD2::Cre mice. In M4D-expressing mice, clozapine-N-oxide increased morphine-induced, but not vehicle-induced, locomotion. In M3D-expressing mice, clozapine-N-oxide blocked morphine-induced, but not vehicle-induced, locomotion. We propose that cholinergic inhibition of rostromedial tegmental GABA neurons via M4 muscarinic receptors facilitates opioid inhibition of the same neurons. This model explains how mesopontine cholinergic systems and muscarinic receptors in the rostromedial tegmental nucleus and ventral tegmental area are important for dopamine-dependent and dopamine-independent opioid-induced rewards and locomotion.
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