Olfactory memory representations are stored in the anterior olfactory nucleus.

The anterior olfactory nucleus (AON) is the initial recipient of odour information from the olfactory bulb, and the target of dense innervation conveying spatiotemporal cues from the hippocampus. We hypothesized that the AON detects the coincidence of these inputs, generating patterns of activity reflective of episodic odour engrams. Using activity-dependent tagging combined with neural manipulation techniques, we reveal that contextually-relevant odour engrams are stored within the AON and that their activity is necessary and sufficient for the behavioural expression of odour memory. Our findings offer a new model for studying the mechanisms underlying memory representations.

Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.

Hippocampal projections to the anterior olfactory nucleus differentially convey spatiotemporal information during episodic odour memory.

The hippocampus is essential for representing spatiotemporal context and establishing its association with the sensory details of daily life to form episodic memories. The olfactory cortex in particular shares exclusive anatomical connections with the hippocampus as a result of their common evolutionary history. Here we selectively inhibit hippocampal projections to the anterior olfactory nucleus (AON) during behavioural tests of contextually cued odour recall. We find that spatial odour memory and temporal odour memory are independently impaired following inhibition of distinct, topographically organized hippocampal-AON pathways. Our results not only reveal a longstanding unknown function for the AON but offer new mechanistic insights regarding the representation of odours in episodic memory.

Activation of Entorhinal Cortical Projections to the Dentate Gyrus Underlies Social Memory Retrieval.

Social interactions are essential to our mental health, and a deficit in social interactions is a hallmark characteristic of numerous brain disorders. Various subregions within the medial temporal lobe have been implicated in social memory, but the underlying mechanisms that tune these neural circuits remain unclear. Here, we demonstrate that optical activation of excitatory entorhinal cortical perforant projections to the dentate gyrus (EC-DG) is necessary and sufficient for social memory retrieval. We further show that inducible disruption of p21-activated kinase (PAK) signaling, a key pathway important for cytoskeletal reorganization, in the EC-DG circuit leads to impairments in synaptic function and social recognition memory, and, importantly, optogenetic activation of the EC-DG terminals reverses the social memory deficits in the transgenic mice. These results provide compelling evidence that activation of the EC-DG pathway underlies social recognition memory recall and that PAK signaling may play a critical role in modulating this process.

Topographic Organization of Hippocampal Inputs to the Anterior Olfactory Nucleus.

Top-down processes conveying contextual information play a major role in shaping odor representations within the olfactory system, yet the underlying mechanisms are poorly understood. The hippocampus (HPC) is a major source of olfactory top-down modulation, providing direct excitatory inputs to the anterior olfactory nucleus (AON). However, HPC-AON projections remain uncharacterized. In an effort to understand how hippocampal inputs are distributed within the AON, we systematically outlined their organization using anterograde and retrograde tracing methods. We found that AON-projecting hippocampal pyramidal neurons are located mostly in the ventral two-thirds of the HPC and are organized topographically such that cells with a ventral to intermediate hippocampal point of origin terminate, respectively, at the medial to lateral AON. Our neuroanatomical findings suggest a potential role for the HPC in the early processing and contextualization of odors which merits further investigation.

Behavioral Evaluation of Odor Memory in Mice.

Behavioural tests based on the spontaneous recognition paradigm have been used extensively for examining the memory capacity of rodents. By exploiting their innate preference to investigate novel stimuli, inferences can be drawn about the perceived familiarity of encountered objects. Olfaction is the dominant sense used by mice to navigate their environment, yet these tests are often conducted using visual objects. By employing odors, one can reduce the high level of variability commonly observed between subjects. In this paper, we describe a protocol for assessing context-dependent odor memory by probing spatial and temporal associations separately or in conjunction with each other. We also detail a context-independent novel odor recognition protocol. These tests offer a simple and effective method for measuring odor memory in rodents using cheap and easily obtained materials.

Bidirectional Control of Anxiety-Related Behaviors in Mice: Role of Inputs Arising from the Ventral Hippocampus to the Lateral Septum and Medial Prefrontal Cortex.

Anxiety is an adaptive response to potentially threatening situations. Exaggerated and uncontrolled anxiety responses become maladaptive and lead to anxiety disorders. Anxiety is shaped by a network of forebrain structures, including the hippocampus, septum, and prefrontal cortex. In particular, neural inputs arising from the ventral hippocampus (vHPC) to the lateral septum (LS) and medial prefrontal cortex (mPFC) are thought to serve as principal components of the anxiety circuit. However, the role of vHPC-to-LS and vHPC-to-mPFC signals in anxiety is unclear, as no study has directly compared their behavioral contribution at circuit level. We targeted LS-projecting vHPC cells and mPFC-projecting vHPC cells by injecting the retrogradely propagating canine adenovirus encoding Cre recombinase into the LS or mPFC, and injecting a Cre-responsive AAV (AAV8-hSyn-FLEX-hM3D or hM4D) into the vHPC. Consequences of manipulating these neurons were examined in well-established tests of anxiety. Chemogenetic manipulation of LS-projecting vHPC cells led to bidirectional changes in anxiety: activation of LS-projecting vHPC cells decreased anxiety whereas inhibition of these cells produced opposite anxiety-promoting effects. The observed anxiety-reducing function of LS-projecting cells was in contrast with the function of mPFC-projecting cells, which promoted anxiety. In addition, double retrograde tracing demonstrated that LS- and mPFC-projecting cells represent two largely anatomically distinct cell groups. Altogether, our findings suggest that the vHPC houses discrete populations of cells that either promote or suppress anxiety through differences in their projection targets. Disruption of the intricate balance in the activity of these two neuron populations may drive inappropriate behavioral responses seen in anxiety disorders.

Top-down modulation of olfactory-guided behaviours by the anterior olfactory nucleus pars medialis and ventral hippocampus.

Olfactory processing is thought to be actively modulated by the top-down input from cortical regions, but the behavioural function of these signals remains unclear. Here we find that cortical feedback from the anterior olfactory nucleus pars medialis (mAON) bidirectionally modulates olfactory sensitivity and olfaction-dependent behaviours. To identify a limbic input that tunes this mAON switch, we further demonstrate that optogenetic stimulation of ventral hippocampal inputs to the mAON is sufficient to alter olfaction-dependent behaviours.