Neurocircuits to Behavior: The New Revolution

Ressler, Kerry J. MD, PhD

doi: 10.1097/HRP.0000000000000152
Advances in Psychiatric Research and Practice 25th Anniversary Brief Communication

*Harvard Medical School and McLean Hospital, Belmont, MA. Email:

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Centuries after the idea that brain regional function was important, among the most transformative concepts in psychiatry over the last several decades is the awareness that distinct neural circuits subserve distinct behavioral functions. In fact, the idea that dynamic activity in distinct circuits underlies specific behaviors is actually fundamental and central to our current models of psychiatric functioning, and the tools to address these circuits have changed rapidly.

Progress since the 1980s in our ability to use the human neuroimaging tools of computed tomography and magnetic resonance imaging to transform understanding of the living human brain is unsurpassed in the history of the neuroscience. The interaction of individual brain regions in a dynamic fashion is now being understood using complex mathematical approaches to examine coactivation with dynamic fMRI. Many of these tools were at an early level of development 25 years ago at the initiation of the Harvard Review of Psychiatry1,2 and are now fully routine in a large area of psychiatric neuroscience.

The tools available for mapping and manipulating circuits in neuroscience model systems—and thus for understanding mechanisms—were fairly consistent for most of the twentieth century. The classic approaches to determine causality were lesion studies; for example, lesioning of the hippocampus in rodents and nonhuman primates established the primacy of this region in declarative memory formation. Other approaches included electrophysiological activation of brain regions and the use of a variety of plant lectins that allowed the visualization of specific axonal paths from one brain region to the next (e.g., Paylay & Chan-Paylay [1976];3 Ralston [1990]4). This technique depended on the observation that these lectins bound to membrane proteins, allowing visualization with antibodies to illuminate the entire axonal and dendritic arbors of individual neurons. Despite the use of these methods over the last decades, various critical tools were still needed to understand the causal functioning of specific circuits: (1) the ability to identify or control specific, genetically identified types of cells, (2) the ability to activate or inhibit certain cells or cell pathways in a temporally precise fashion, (3) the ability to control specific cell types or cell pathways with systemic drug manipulation, and (4) the ability to combine genetic tools with cell-type and circuit-based tools. A full understanding of how specific circuits create specific behaviors would require new tools to answer these questions. A number of such breakthroughs in the last decade have radically transformed how we approach the neuroscience of behavior.

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A number of different innovations have led to the current transformative toolbox available to behavioral neuroscientists. The first innovation, however, was the molecular biology revolution, which has led to a large number of molecular genetic tools—beginning with transgenic mice in which specific cell populations express different genes that provide a wide range of abilities to delete or overexpress gene targets of interest.

Genetically modified viral vectors have more recently broadened the ability to express genes of interest (e.g., Heldt & Ressler [2009]5). Combined with the region specificity of viral infusions, along with intersectional approaches that combine viruses with transgenic animals, even more powerful tools are available to target anterograde and retrograde processes, as well as a variety of cell types. One common approach uses modified viruses such as adeno-associated virus, lentivirus, and herpes simplex virus, all of which can be easily altered with modern molecular engineering techniques, allowing a now huge range of inducible manipulations. Other approaches make use of specific cell types, gene overexpression, mutant gene expression, inducible deletion, expressing-antisense and other noncoding RNAs, along with epigenetic regulation. Intersectional trans-synaptic approaches are also now in use.

The newest and possibly most transformative tools in recent years are optogenetic and chemogenetic approaches to actively manipulate targeted neurons. This toolbox allows a mechanistic approach to determining temporally specific, cell-type specific, and circuit-specific neural regulation of behaviors. Thus, researchers are beginning to dissect the neuronal basis of behavior, at the levels of epigenetics, genetics, neural circuits, and dynamic-behavioral regulation. By understanding the basic neuroscience principles underlying mammalian behavior, scientists are making progress in translating the mechanisms of behavior to novel biology-based interventions.

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Optogenetic Approaches

Optogenetics—the control of neuronal firing through genetically controlled, molecularly engineered, light-sensitive ion channels—has truly transformed neuroscience within the past decade. While several are credited with its discovery and initial implementation, Karl Deisseroth, a psychiatrist physician-scientist from Stanford, is widely regarded as being most central to the innovation and dissemination of these techniques for dissecting neural circuits related to behavior (Boyden et al. [2005];6 Deisseroth [2015]7).

Years earlier, genes encoding several different species of “opsin” (light-sensitive) receptors had been identified in algae and other simple organisms. It was known that some of these receptors could be expressed in mammalian neurons with no adverse consequences, but when certain wavelengths of light (using fiber-optic technology) were delivered to these neurons, they would fire action potentials. The initial versions of these “excitatory” optogenetic channels were members of the “channel rhodopsin” family. In parallel, a set of inhibitory channels were identified, initially of the “halorhodopsin” family. Since the initial discovery, many additional protein channels have been identified, leading to a large array of specific tools for controlling neuronal activity in precise ways.

Current therapies lack such a cellular or temporal level of precision. Deep-brain stimulation, for example, has been a powerful innovation for a number of refractory neuropsychiatric syndromes, including depression. Such stimulation, however, while much more targeted regionally to neural circuits than ECT and transcranial magnetic stimulation, is still crude from the perspective of what we now know about microcircuits within neural regions. One imagines the possibility of a future psychiatric toolbox of cell-type specific, optogenetically regulated processes that drive specific behavioral microcircuits.

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Chemogenetic Approaches

A complementary approach to optogenetics, also advanced within the last decade, is the concept of chemogenetics, with the most robust model being DREADD technology (designer receptors exclusively activated by designer drugs) (Nawaratne et al. [2008];8 Roth [2016]9). Instead of using light energy to directly activate ion channels, chemogenetic approaches use genetically modified G-protein-coupled receptors activated by otherwise inert drugs. The specific drug can then be delivered systemically or directly to the brain region of interest. Compared to optogenetics, chemogenetics has the distinct properties of (1) being activated via a systemic drug not needing indwelling fiber optics into the brain, and (2) activating cells in a more naturalistic, modulatory fashion with second-messenger pathways rather than directly stimulating them or inhibiting them. Thus, while optogenetic approaches may provide both better understanding of the biophysics and direct connectivity of different neuronal systems, chemogenetic approaches may provide a better tool for understanding neurotransmitter-based modulation.

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These advances would have looked like science fiction at the time of the founding of HRP just 25 years ago. While many of our diagnoses, psychotherapies, and even medications used for psychiatric disorders are similar to what was available in the early 1990s, the way that modern neuroscientists approach dissecting the neural circuits underlying the mammalian brain and behavior has truly been transformed. It is astounding that, with a light pulse or an otherwise inert, targeted drug, we now have tools to routinely switch “on” and “off” specific neurons within specific microcircuits of specific brain areas.

Such a basic understanding of the basis of behavior is critical for progress. An appreciation of the biology of bacteria and viruses was needed before modern medicine could exert control over infectious diseases. An understanding of basic biology of cell division and growth regulation was required for the modern evolution in cancer biology and mechanism-based targets in cancer treatment. Similarly, an understanding of the neural mechanisms (at the circuit, cell, and gene-expression levels) is required before we can derive novel and powerful therapeutics targeting the cellular basis of specific behaviors.

This revolution in psychiatric neuroscience is already changing our understanding of, and approach to, behavioral neuroscience and disorders related to neural circuitry (e.g., psychiatric disease). It is difficult to know how thoroughly these approaches will alter the landscape of psychiatry, but it will assuredly be profound. At the molecular and cellular levels, new approaches are actively being pursued that will allow receptor-based target identification, verification, and validation of new compounds that—rather than being identified by a peculiar rodent behavior of questionable relevance to the human condition—are instead based on shared neural circuitry and genetic commonality.

Furthermore, as implied above, the neurotherapeutics revolution may allow an extreme possibility of precision medicine. For example, current molecular genetic technology could lead to a single surgery for a one-time, molecularly engineered virus manipulation of cell-type specific microcircuits that are dysregulated in one individual’s brain, after which that person could take a pill to directly switch on, turn off, or otherwise modulate that precise microcircuit—directly modifying previously aversive, anhedonic, habitual, or other dysregulated processes. This is truly the stuff of science fiction.

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The neurocircuitry therapeutics revolution is rapidly advancing. The tools, from molecular engineered, cell-type specific viruses to optogenetics and chemogenetics, continue to evolve rapidly and to transform the field of behavioral and functional neuroscience. The field of psychiatry will need to equally rapidly develop an ethics of how to use these approaches. Furthermore, we must develop new theories and broader perspectives to understand how the circuit dynamics underlying behavior fit, for example, within our current understanding of monaminergic modulation of depression and psychosis. Even more, how do these perspectives complement our psychodynamic and behavioral psychotherapies and models of human behavior? Regardless of one’s perspective, there is no doubt that a revolution is under way in the neuroscience of psychiatry. Our field, our therapeutics, and our ability to treat disease will most certainly appear drastically different in another 25 years from now.

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Declaration of interest

The author reports no conflicts of interest: The author alone is responsible for the content and writing of the article.

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DREADD; neuron, neuroscience; optogenetic; viral vector

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