Targeting Neural Circuits

Abstract

Current optogenetic methodology enables precise inhibition or excitation of neural circuits, spanning timescales as needed from the acute (milliseconds) to the chronic (many days or more), for experimental modulation of network activity and animal behavior. Such broad temporal versatility, unique to optogenetic control, is particularly powerful when combined with brain activity measurements that span both acute and chronic timescales as well. This enables, for instance, the study of adaptive circuit dynamics across the intact brain, and tuning interventions to match activity patterns naturally observed during behavior in the same individual. Although the impact of this approach has been greater on basic research than on clinical translation, it is natural to ask if specific neural circuit activity patterns discovered to be involved in controlling adaptive or maladaptive behaviors could become targets for treatment of neuropsychiatric diseases. Here we consider the landscape of such ideas related to therapeutic targeting of circuit dynamics, taking note of developments not only in optical but also in ultrasonic, magnetic, and thermal methods. We note the recent emergence of first-in-kind optogenetically-guided clinical outcomes, as well as opportunities related to the integration of interventions and readouts spanning diverse circuit-physiology, molecular, and behavioral modalities.

Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man

“…The hope of using more targeted methodologies to modulate circuits remains. Nevertheless, these ideas are currently largely theoretical and are limited by our understanding of the neural circuitry, which lends urgency to the development of technological innovation in this area 163 .…”

The need for calcium imaging in nonhuman primates: New motor neuroscience and brain-machine interfaces

“…During this behavioral task, two-photon or (widefield epifluorescence) microscopy can be used to capture the optical activity readout of neural populations in the field of view ([fig1:2p]). Finally post-mortem histology can be performed using CLARITY ([fig1:clarity]), a clearing technique which preserves the 3d arrangement of cells and provides information about cell type and projection patterns via immunostaining (Chung et al 2013; Rajasethupathy, Ferenczi, and Deisseroth 2016; Lerner, Ye, and Deisseroth 2016). …”

Circuitry-Based Human Neuroanatomy for the Next Generation in Psychiatry and Neuroscience

“…2). Once functional connectomes are mapped, they may provide some ways toward fixing altered circuitry, which would in turn ameliorate behavioral symptoms [23,24]. In fact, this is the strategy/translational roadmap proposed by Dr. Joshua Gordon, the head of the NIMH [25].…”

“…This knowledge is now applied to potential therapeutic approaches to posttraumatic stress disorder, an aberrant behavioral response associated with fear memory [30]. Recent techniques such as optogenetics, deep brain stimulation, and transcranial magnetic stimulation have great potential for circuitry-based interventions in psychiatric disorders [23,24]. In fact, deep brain stimulation and transcranial magnetic stimulation have been approved for use in treatment-resistant depression, and other disorders including drug addiction may be in sight for clinical application (Fig.…”