Ventral Hippocampal Inputs Preferentially Drive Corticocortical Neurons in the Infralimbic Prefrontal Cortex

Abstract

Inputs from the ventral hippocampus (vHPC) to the prefrontal cortex (PFC) play a key role in working memory and emotional control. However, little is known about how excitatory inputs from the vHPC engage different populations of neurons in the PFC. Here we use optogenetics and whole-cell recordings to study the cell-type specificity of synaptic connections in acute slices from the mouse PFC. We first show that vHPC inputs target pyramidal neurons whose cell bodies are located in layer (L)2/3 and L5 of infralimbic (IL) PFC, but only in L5 of prelimbic (PL) PFC, and not L6 of either IL or PL. We then compare connections onto different classes of projection neurons located in these layers and subregions of PFC. We establish vHPC inputs similarly contact corticocortical (CC) and cortico-amygdala neurons in L2/3 of IL, but preferentially target CC neurons over cortico-pontine neurons in L5 of both IL and PL. Of all these neurons, we determine that vHPC inputs are most effective at driving action potential (AP) firing of CC neurons in L5 of IL. We also show this connection exhibits frequency-dependent facilitation, with repetitive activity enhancing AP firing of IL L5 CC neurons, even in the presence of feedforward inhibition. Our findings reveal how vHPC inputs engage defined populations of projection neurons in the PFC, allowing preferentially activation of the intratelencephalic network. We examined the impact of connections from the ventral hippocampus (vHPC) onto different projection neurons in the mouse prefrontal cortex (PFC). We found vHPC inputs were strongest at corticocortical neurons in layer 5 of infralimbic PFC, where they robustly evoked action potential firing, including during repetitive activity with intact feedforward inhibition.

Hippocampal inputs engage CCK+ interneurons to mediate endocannabinoid-modulated feed-forward inhibition in the prefrontal cortex

“…To isolate monosynaptic connections, we 274 included TTX (1 μM), 4-AP (10 μM), and elevated Ca 2+ (4 mM), which blocks action potentials 275 (APs) but restores presynaptic release (Little and Carter, 2012;Petreanu et al, 2009). We also 276 kept the light intensity and duration constant within pairs, allowing us to account for differences in 277 viral expression across animals and slices (Liu and Carter, 2018). We found that vHPC inputs 278 evoked robust EPSCs at CCK+ interneurons, which were similar in amplitude to IT cells ( Fig.…”

“…The vHPC primarily projects to the ventral medial PFC in rodents, with axons most prominent in 55 layer 5 (L5) of infralimbic (IL) PFC (Phillips et al, 2019). These excitatory inputs contact multiple 56 populations of pyramidal cells, and are much stronger at intratelencephalic (IT) cells than nearby 57 pyramidal tract (PT) cells (Liu and Carter, 2018). vHPC inputs can drive robust firing of IT cells 58 (Liu and Carter, 2018), which may be important for maintaining activity during behavioral tasks 59 (Padilla-Coreano et al, 2016; Spellman et al, 2015).…”

“…These excitatory inputs contact multiple 56 populations of pyramidal cells, and are much stronger at intratelencephalic (IT) cells than nearby 57 pyramidal tract (PT) cells (Liu and Carter, 2018). vHPC inputs can drive robust firing of IT cells 58 (Liu and Carter, 2018), which may be important for maintaining activity during behavioral tasks 59 (Padilla-Coreano et al, 2016; Spellman et al, 2015). However, they also evoke prominent feed-60 forward inhibition at pyramidal cells (Marek et al, 2018), with excitation and inhibition evolving 61 with different dynamics (Liu and Carter, 2018).…”

“…vHPC inputs can drive robust firing of IT cells 58 (Liu and Carter, 2018), which may be important for maintaining activity during behavioral tasks 59 (Padilla-Coreano et al, 2016; Spellman et al, 2015). However, they also evoke prominent feed-60 forward inhibition at pyramidal cells (Marek et al, 2018), with excitation and inhibition evolving 61 with different dynamics (Liu and Carter, 2018). Here we focus on the mechanisms responsible for 62 this inhibition by establishing which interneurons are engaged by vHPC inputs to the PFC.…”

“…To study connectivity, we injected 271 AAV-ChR2-YFP into the vHPC and recorded EPSCs from identified interneurons. To compare 272 across animals and cell types, we recorded from neighboring IT cells within the same slice, which 273 receive the bulk of vHPC inputs (Liu and Carter, 2018). To isolate monosynaptic connections, we 274 included TTX (1 μM), 4-AP (10 μM), and elevated Ca 2+ (4 mM), which blocks action potentials 275 (APs) but restores presynaptic release (Little and Carter, 2012;Petreanu et al, 2009).…”