Cholinergic modulation of grid cell activity in the entorhinal cortex of mice
Final Report Abstract
The overall aim of this project addressed neuronal mechanisms underlying the coding of location and movement speed in the medial entorhinal cortex (MEC) and modulation of neuronal coding mechanisms by cholinergic medial septum inputs. The initial major specific aim focused on investigating a long-standing question in the field of cognitive neuroscience, namely how grid cell firing characteristics are modulated by cholinergic signaling. The scientific strategy to address this question was an inhibitory approach to test the functional impact of cholinergic projection neurons in the medial septum/diagonal band of Broca (MSDB) on single unit firing characteristics in the MEC. To address this scientific question, we used an innovative approach combining multiple single unit recordings in MEC and optogenetic inhibition of cholinergic projection neurons in the medial septum. During recording sessions, mice were randomly foraging for cereal bits in a 1 m2 open-field environment, while being tracked using a ceilingmounted infrared camera and head-mounted LEDs emitting invisible infrared light. Using an LED bar with a small and big infrared LED at each end allowed the tracking of head direction along with the tracking of spatial position and running speed. To control for the effectiveness of our optogenetic inhibition approach and to further control for cholinergic effects potentially mediated via an intraseptal relay, we also acquired data from wildtype mice, transgenic vGluT2-Cre mice, and PV-Cre mice, where ArchT expression was targeted to all medial septal neurons, vGluT2-positive glutamatergic projection neurons, or PV-positive GABAergic MSDB projection neurons, respectively. We successfully achieved recordings of neuronal activity in combination with sufficient optogenetic inhibition of MSDB neurons and sufficient coverage of the open field environment in a total of 20 mice, including 4 wildtype mice, 10 ChAT-Cre mice, 3 PV-Cre mice, and 3 vGluT2-Cre mice. Furthermore, we performed recordings in additional 5 ChAT-Cre control mice expressing GFP instead of ArchT in MSDB cholinergic neurons. In total, we identified 526 single units in our recordings of neuronal activity in the MEC of freely exploring mice. Despite this large number of single units from multiple mice, our data set did not contain a large enough number of grid cells for the analysis of cholinergic modulation of grid cell firing properties. However, computational models employ a linear running speed signal to maintain the spatial periodicity of grid cell firing and update the animal’s location via path integration. Computational models have also suggested a possible role of cholinergic modulation in the coding of running speed in the entorhinal cortex. Analyzing the firing properties of MEC neurons revealed that we recorded a large number of speed cells in the MEC from multiple mice of wildtype and different transgenic backgrounds. In line with our overall goal of investigating the potential roles of cholinergic modulation in the neural coding of location and movement speed, we therefore decided to make use of our data set and switched our focus of analysis to studying the effects of optogenetic inhibition of MSDB neurons on speed cells in the MEC. This study was innovative because I used signal processing analysis techniques to analyze changes in firing rate at different time scales, which allowed me to address the important question of how temporally accurate a speed code by firing rate can be. One major finding of this study was that the running speed code by firing rate differs across time scales and that speed cells in the entorhinal cortex are modulated by, but do not code for running speed in real-time. This finding is expected to have major consequences on models of path integration and our understanding of firing rate codes in the brain. A second major finding of this study was that the speed code by firing rate does not depend on medial septum inputs.
Publications
-
(2017) Models of spatial and temporal dimensions of memory. Current Opinion in Behavioral Sciences 17:27–33
Hasselmo ME, Hinman JR, Dannenberg H, Stern CE
-
(2017) Modulation of Hippocampal Circuits by Muscarinic and Nicotinic Receptors. Front Neural Circuits 11:102
Dannenberg H, Young K, Hasselmo M
-
(2018) Specific Basal Forebrain-Cortical Cholinergic Circuits Coordinate Cognitive Operations. J Neurosci 38:9446–9458
Záborszky L, Gombkoto P, Varsanyi P, Gielow MR, Poe G, Role LW, Ananth M, Rajebhosale P, Talmage DA, Hasselmo ME, Dannenberg H, Minces VH, Chiba AA
-
(2019) The firing rate speed code of entorhinal speed cells differs across behaviorally relevant time scales and does not depend on medial septum inputs. J Neurosci. 39:3434–3453
Dannenberg H, Kelley C, Hoyland A, Monaghan CK, Hasselmo ME
