Optogenetic behavioral studies in depression research: A systematic review

Abstract

Optogenetics has made substantial contributions to our understanding of the mechanistic underpinnings of depression. This systematic review employs quantitative analysis to investigate the impact of optogenetic stimulation in mice and rats on behavioral alterations in social interaction, sucrose consumption, and mobility. The review analyses optogenetic behavioral studies using standardized behavioral tests to detect behavioral changes induced via optogenetic stimulation in stressed or stress-naive mice and rats. Behavioral changes were evaluated as either positive, negative, or not effective. The analysis comprises the outcomes of 248 behavioral tests of 168 studies described in 37 articles, including negative and null results. Test outcomes were compared for each behavior, depending on the animal cohort, applied type of stimulation and the stimulated neuronal circuit and cell type. The presented synthesis contributes toward a comprehensive picture of optogenetic behavioral research in the context of depression.

Keywords: Behavioral neuroscience; Techniques in neuroscience.

Graphical abstract

Figure 1

Schematic illustration depicting the procedure for assessing the impact of optogenetic stimulation on specific behaviors Social interaction, sucrose consumption, and mobility are investigated in the social interaction test (SIT), the sucrose preference test (SPT), and the forced swim test (FST) or tail suspension test (TST), respectively. Behavioral changes are indicated through alterations in test-specific outcome measures and are evaluated as having a positive effect, a negative effect, or no behavioral effect.

Figure 2

Prisma Flow Diagram

Figure 3

Outcomes of optogenetic behavioral tests Quantities of performed behavioral tests with a positive, negative, or no behavioral effect (A) investigating social interaction, sucrose consumption, and mobility, (B) performed using stressed or stress-naive animals, (C) in which an activating or inhibitory stimulation protocol was applied, (D) for different stimulated brain targets.

Figure 4

Effects of stimulated neuronal circuits on behavioral outcomes Overview of all performed optogenetic behavioral tests exclusively in stressed cohorts for (A) social interaction, (B) sucrose consumption and (C) mobility, depending on the outcome (first circle), the applied type of stimulation (activation vs. inhibition) (second circle), stimulation target (third circle) and neuronal types (outer circle). The numbers in parantheses indicate the total number of conducted tests. Dashed lines (black) indicate portion of tests, in which optogenetic activation or inhibition caused a positive outcome.

Figure 5

Optogenetic modulation of neuronal circuits in stressed animals Schematic illustration of neuron projections and local neuron populations, in which optogenetic stimulation had a positive behavioral effect, in stressed animals for (A) social interaction, (B) sucrose preference and (C) mobility. Solid lines illustrate optogenetic activation. Dashed lines illustrate optogenetic inhibition. Encircled areas indicate the stimulation of local neuron populations. Arrows indicate the stimulation of neuron projections. Different colors indicate different populations of neurons, in case specific subtypes of projections or local neurons were stimulated within a circuit or a local area. Black lines indicate the stimulation of neuron projections or local neurons without further specification of neuronal subtypes. For example, regarding social interaction VTA-mPFC, mPFC-NAc, mPFC-vSTR, mPFC-DRN projections, and local neurons within the mPFC were stimulated as follows: Specifically dopamine neuron projections from the VTA to the mPFC were activated, specifically glutamate neuron projections from the mPFC to the NAc were activated, neuron projections from the mPFC to the vSTR were activated, neuron projections from the mPFC to the DRN were inhibited and local mPFC neurons were activated.