Form Meets Function in the Brain: Observing the Activity and Structure of Specific Neural Connections

Abstract

Recent advances in neuroscience have enabled increasingly detailed insight into the activity and structure of brain circuitry. In previous work, we have developed and applied methods for precisely controlling the activity of specific cells and projections within neural systems during behavior (optogenetics). Here I review distinct complementary technological approaches for observing natural activity patterns in these cells and projections during behavior (fiber photometry) and for obtaining anatomical insights into the wiring and molecular phenotype of these circuit elements within the intact mammalian brain (CLARITY-optimized lightsheet microscopy). Together these approaches may help further advance understanding of the circuit dynamics and wiring patterns that underlie adaptive and maladaptive behavior.

Genetic Reporters of Neuronal Activity: c-Fos and G-CaMP6

“…Moreover, the deeper the area of interest, the greater the required illumination, increasing the risk of photodamage to tissue, increasing the rate of photobleaching of the fluorophoer, and decreasing the signal-to-noise due to surface reflections of the illumination. Fiber photometry offers an opportunity to utilize GCaMP6 to image deeper structures, but the spatial resolution of the data suffers and most reported systems should be thought of as reporting an average calcium concentration for a local population rather than the sub-neuron resolution capable with 2-photon resonant scanning microscopes (Deisseroth, 2016; Liang et al, 2017). This technology may still have potential when combined with novel imaging approaches, however, for simultaneous imaging of spatially separated areas (Kim et al, 2016) and is the focus of ongoing technique development.…”

A Custom Made Electrode Construct and Reliable Implantation Method That Allows for Long-Term Bilateral Deep Brain Stimulation in Mice

“…Therefore, mechanisms underlying DBS can be further investigated by using transgenic mouse lines. By using transgenic mouse models in combination with state of the art techniques (e.g., optogenetics, fiber photometry, Designer Receptors Exclusively Activated by Designer Drug), molecular, cellular, and network manipulations can be applied and recorded to better understand the impact of DBS on the brain (37)(38)(39). This would not be possible in other animal species.…”

Focus on females: a less biased approach for studying strategies and mechanisms of memory

“…Exploratory research to determine what transcriptional, signaling, and neural loci are activated in females during learning, memory consolidation, and memory retrieval will be critical for identifying mechanisms and circuits that are not engaged by males. Recent advances in sequencing [64] and technologies for quantifying brain-wide activation (e.g., CLARITY; [65,66]) provide powerful, broad-based screening methods. Applying these tools in both sexes will identify novel mechanisms of learning and memory processes, additional targets for female-centric approaches to studying sex differences in memory, and insights into possible cognitive strategies engaged by females in learning and memory tasks.…”