Let there be light: linking neural circuit activity and behavior via an “all-optical” approach

Dr. Michael Hausser is a Wellcome Principal Research Fellow and Professor of Neuroscience at University College London. The Hausser lab combines cellular and systems neuroscience in order to examine neural circuit computations at the cellular level in the mammalian brain, with a special focus on the role of dendrites. In 2015, Dr. Hausser was elected a Fellow of the Royal Society for his fundamental contributions to our understanding of how dendrites contribute to computation in the mammalian brain, presenting dendrites as independent processing and signaling units that perform local computations. Dr. Hausser’s group aims to establish a causal link between neural circuit activity and behavior and is addressing this goal by employing an “all-optical” approach, enabling concurrent readout and manipulation of neural circuit activity.

The Hausser lab recently demonstrated the utility of this approach in work published in 2020, titled “Targeted Activation of Hippocampal Place Cells Drives Memory-Guided Spatial Behavior.” Hippocampal place cells are pyramidal neurons that exhibit location-specific firing, and populations of these cells form unique maps that represent a given environment. Place cell activity can encode information about an experience, and primarily correlational evidence has shown that generation of place cell firing sequences supports spatial navigation and episodic memory formation. This study demonstrated a causal role for hippocampal place cell activity in memory-guided spatial navigation. The authors utilized an “all-optical” combination of simultaneous two-photon calcium imaging and two-photon targeted optogenetics in head-fixed mice performing a virtual reality spatial navigation task (Graphical Abstract). This allowed them to both record and stimulate various populations of place cells that encode distinct behaviorally relevant locations and thus assess their role in guiding spatial behavior. The authors hypothesized that stimulating a population of similarly tuned place cells would drive mice to exhibit the behavior that is normally carried out in the location of those cells’ place fields.

Graphical Abstract

First, mice were trained to perform a virtual reality spatial navigation task that required them to stop and lick in a specific reward zone on a virtual linear track in order to receive a reward (Figures 1C-1E). As the mice executed this task, the authors performed two-photon calcium imaging to identify cells with a place field on the virtual track (Figures 1F and 1G) and then categorized place cells with fields that covered the reward zone and start zone as reward-zone place cells (Reward-PCs) and start zone place cells (Start-PCs), respectively. Reward-PC activity corresponded to high lick rate and decelerated running speed, whereas Start-PC activity was associated with low lick rate and stable high running speed. During stimulation sessions, two-photon optogenetics was used to activate specific place cell populations (Start-PCs, Reward-PCs) as the mouse crossed the central stimulation point.

Figure 1: All-Optical Manipulation of Place Cells during Spatial Navigation in Virtual Reality

The authors found that stimulating Reward-PCs in a location preceding the reward zone and their endogenous firing fields caused an increase in lick rate in comparison to the behavioral baseline in the stimulation zone (Figures 2B and 2C). Thus, the animal’s behavior was biased toward that which was normally exhibited in the reward zone. This demonstrates that reward-zone place cell activity has a causal role in driving spatial behavior. Furthermore, Start-PC stimulation, which occurs in a location beyond their endogenous firing fields, resulted in an increase in the proportion of trials where the mouse ran past the reward zone, and these trials were accompanied by a decrease in reward zone licking (Figures 2K and 2L). This shows that Start-PC stimulation has a behavioral effect that occurs after stimulation has stopped, suggesting an ongoing impact on neural activity. The authors additionally demonstrated that place cell stimulation inhibits endogenous place code expression and triggers remapping.

Figure 2: Targeted Stimulation of Reward-Zone Place Cells Drives Reward-Zone-Related Behavior

The aforementioned work demonstrates the exciting potential for “all-optical” strategies in probing neural circuit dynamics and identifying causal relationships between behavior and neural circuit activity.

To learn more about Dr. Hausser’s work, please join us for the talk, “Forging Causal Links between Neural Circuit Activity and Behavior,” on Tuesday, May 18^th at 12pm on Zoom.

Zoom: https://uchealth.zoom.us/j/81547662915

References:

1. Dalgleish HW, Russell LE, Packer AM, Roth A, Gauld OM, Greenstreet F, Thompson EJ, Häusser M. How many neurons are sufficient for perception of cortical activity? Elife. 2020 Oct 26;9:e58889. doi: 10.7554/eLife.58889. PMID: 33103656; PMCID: PMC7695456.
2. Emiliani V, Cohen AE, Deisseroth K, Häusser M. All-Optical Interrogation of Neural Circuits. J Neurosci. 2015 Oct 14;35(41):13917-26. doi: 10.1523/JNEUROSCI.2916-15.2015. PMID: 26468193; PMCID: PMC4604230.
3. Robinson NTM, Descamps LAL, Russell LE, Buchholz MO, Bicknell BA, Antonov GK, Lau JYN, Nutbrown R, Schmidt-Hieber C, Häusser M. Targeted Activation of Hippocampal Place Cells Drives Memory-Guided Spatial Behavior. Cell. 2020 Dec 10;183(6):1586-1599.e10. doi: 10.1016/j.cell.2020.09.061. Epub 2020 Nov 6. Erratum in: Cell. 2020 Dec 23;183(7):2041-2042. PMID: 33159859; PMCID: PMC7754708.
4. Russell LE, Yang Z, Tan PL, et al. The influence of visual cortex on perception is modulated by behavioural state. bioRxiv; 2019. DOI: 10.1101/706010.

Hausser Lab Website: http://www.dendrites.org/

Audrey Miglietta is a first year PhD student in the Neurosciences Graduate Program at UCSD, currently rotating in the lab of Dr. Richard Daneman.