Dedicated Hippocampal Inhibitory Networks for Locomotion and Immobility

Abstract

Network activity is strongly tied to animal movement; however, hippocampal circuits selectively engaged during locomotion or immobility remain poorly characterized. Here we examined whether distinct locomotor states are encoded differentially in genetically defined classes of hippocampal interneurons. To characterize the relationship between interneuron activity and movement, we used , two-photon calcium imaging in CA1 of male and female mice, as animals performed a virtual-reality (VR) track running task. We found that activity in most somatostatin-expressing and parvalbumin-expressing interneurons positively correlated with locomotion. Surprisingly, nearly one in five somatostatin or one in seven parvalbumin interneurons were inhibited during locomotion and activated during periods of immobility. Anatomically, the somata of somatostatin immobility-activated neurons were smaller than those of movement-activated neurons. Furthermore, immobility-activated interneurons were distributed across cell layers, with somatostatin-expressing cells predominantly in stratum oriens and parvalbumin-expressing cells mostly in stratum pyramidale. Importantly, each cell's correlation between activity and movement was stable both over time and across VR environments. Our findings suggest that hippocampal interneuronal microcircuits are preferentially active during either movement or immobility periods. These inhibitory networks may regulate information flow in "labeled lines" within the hippocampus to process information during distinct behavioral states. The hippocampus is required for learning and memory. Movement controls network activity in the hippocampus but it's unclear how hippocampal neurons encode movement state. We investigated neural circuits active during locomotion and immobility and found interneurons were selectively active during movement or stopped periods, but not both. Each cell's response to locomotion was consistent across time and environments, suggesting there are separate dedicated circuits for processing information during locomotion and immobility. Understanding how the hippocampus switches between different network configurations may lead to therapeutic approaches to hippocampal-dependent dysfunctions, such as Alzheimer's disease or cognitive decline.

Structured Inhibitory Activity Dynamics During Learning

“…This correlation was strong on Day 1, and strikingly, this correlation was significant across all days of the remapping protocol ( Figure 5A, Day 1, Pearson's Correlation=0.697, p<0.001; Day 2, r=0.668, p<0.001; Day 3, r=0.764 p<0.001; Day 5, r=0.583 p<0.001). We have previously verified place cell global remapping across different virtual environments in this task (Arriaga and Han, 2017), strongly suggesting that this consistent functional inhibitory network structure occurs despite differing ensembles of activated pyramidal neurons. A trivial explanation for these results could be that this correlation results from general similarities across the two behavioral epochs, such as having equivalent tasks or shared layout of the virtual worlds.…”

“…Calcium activity can be taken as a proxy for neuronal activity as multiple studies using simultaneous in vivo imaging and cell-attached patch electrophysiology on the same neurons have found strong correlation between spiking and calcium signals (Chen et al, 2013;Dana et al, 2016). We, and others, have measured the activity dynamics and coding properties of hippocampal neurons in visual virtual environments and found significant similarity between VR and real world behavior in several aspects of function such as place coding, directionspecificity, place cell remapping in novel environments, and interneuron activity correlation and anti-correlation with locomotion (Arriaga and Han, 2017;Harvey et al, 2009;Sheffield et al, 2017).…”

“…To investigate in vivo interneuronal activity dynamics during exposure to novel environments, we used two-photon imaging of neuronal calcium activity during a spatial navigation task in visual virtual reality (VR) (Arriaga and Han, 2017). We used an electric tunable lens to image a 3-D volume of mouse hippocampal CA1 by capturing sequential imaging frames along the z-axis moving from ventral to dorsal.…”

“…A possible confound to this interpretation would be decreased locomotion in New. Many SOM-ints have activity that is positively correlated with locomotion, although there is a distinct population that is anti-correlated (Arriaga and Han, 2017). Thus, it is possible that decreased interneuron activity is due to decreased locomotion in New that gradually recovers over repeated exposure.…”

“…An alternate possibility is that individual interneurons play consistent and reproducible roles during learning, reflecting an underlying structure in how inhibition regulates the network. While inhibitory neurons are composed of multiple cell-types playing distinct network roles (Klausberger and Somogyi, 2008;Pelkey et al, 2017), little is known about the functional specialization of interneurons within a defined cell-type (Arriaga and Han, 2017).…”