Ventral hippocampal projections to the medial prefrontal cortex regulate social memory

Abstract

Inputs from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC) have been implicated in several neuropsychiatric disorders. Here, we show that the long-range vHIP-mPFC projection is hyperactive in the Mecp2 knockout (KO) mouse model of the autism spectrum disorder Rett syndrome, which has deficits in social memory. Chronically mimicking vHIP-mPFC hyperexcitability in wild-type mice impaired social memory, whereas chronic inhibition of mPFC-projecting vHIP neurons in Mecp2 KO mice rescued social memory deficits; the extent of memory rescue was negatively correlated with the strength of vHIP input to the mPFC. Acute manipulations of the vHIP-mPFC projection also affected social memory in a specific and selective manner, suggesting that proper vHIP-mPFC signaling is necessary to recall social memories. In addition, we identified an altered vHIP-mPFC innervation pattern and increased synaptic strength onto layer 5 pyramidal neurons as contributing factors in aberrant vHIP-mPFC signaling in Mecp2 KO mice. Phillips et al. vHIP-mPFC projection regulates social memoryPREPRINT dyes, intracellular recordings, and dual-color optogenetics, we showed that the long-range vHIP-mPFC projection is hyperactive in RTT mice, which results in social memory deficits. Furthermore, chemogenetic manipulation of mPFC-projecting vHIP neurons in wild-type (WT) and RTT mice correlated with social memory performance in a specific and selective manner. Lastly, these behavioral consequences arose from alterations in the morphology and function of excitatory synapses between vHIP axons and pyramidal neurons in layer 5 of the mPFC. RESULTS mPFC-projecting vHIP neurons are selectively activated during social encountersBecause both the vHIP and mPFC have been independently implicated in different aspects of social behavior (Hitti and Siegelbaum, 2014;Liang et al., 2018;Meira et al., 2018;Okuyama et al., 2016;Selimbeyoglu et al., 2017;Yizhar et al., 2011), we first tested if the vHIP projection to the mPFC is selectively engaged during social encounters. To identify vHIP neurons based on their long-range projections, we bilaterally injected green RetroBeads into the prelimbic (PL) region of the mPFC and red RetroBeads into the lateral hypothalamus (LH) of male WT and Mecp2 KO mice at postnatal day 31 (P31), and then we allowed 14 days for RetroBead transfer until P45, when male Mecp2 KO mice are symptomatic (Chen et al., 2001) (Figures 1A and 1B). We placed mice into a testing chamber, where they were sequentially exposed to either two inanimate objects (two novel fake mice) or to other live mice (a co-housed WT littermate and a novel age-matched WT mouse). Forty-five minutes after the last interaction, we perfused the mice and prepared the brain for quantitative immunohistochemistry of the immediate early gene c-Fos as an estimate of neuronal activity ( Figures 1C and 1D). All vHIP neurons in WT mice that interacted with other mice showed higher c-Fos intensities than those in mice that interacted with inanimate objects, irrespect...

The Hippocampus and Social Impairment in Psychiatric Disorders

“…Projections from vCA1 pyramidal neurons to nucleus accumbens shell are necessary for social recognition (Okuyama et al 2016), and plasticity in this pathway modulates social reward and affiliation (Walum and Young 2018). Projections from vCA1 to medial prefrontal cortex (mPFC) are also necessary for social recognition and likely reflect social memory retrieval (Phillips et al 2018), in agreement with a proposed role for mPFC in retrieving hippocampal representations to guide decision-making . Indeed, mPFC to dorsal periaqueductal gray circuitry directly modulates social behaviors (Franklin et al 2017).…”

“…Individuals with ASD have metabolic abnormalities in the hippocampus that correlate with social impairment (Endo et al 2007), and white matter tracts are altered between the hippocampus and mid-fusiform gyrus, a pathway important to face processing (Conturo et al 2008). In a mouse model of ASD, hyperactivity of vCA1 (anterior in humans) to prelimbic mPFC projections relate to impaired social memory (Phillips et al 2018), suggesting posterior CA2 to anterior CA1 (dCA2-vCA1 in rodents) to mPFC circuitry may be relevant to ASD etiology. Indeed, in another animal model, a synaptic gene (SHANK3) mutation that commonly results in ASD diagnosis reduced synaptic plasticity in a CA1-prelimbic mPFC pathway and selectively impaired long-term social memory-deficits that were reduced with oxytocin administration (Harony-Nicolas et al 2017).…”