Towards new approaches to disorders of fear and anxiety

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Fear and anxiety are debilitating conditions that affect a significant number of individuals in their lifetimes. Understanding underlying mechanisms of these disorders affords us the possibility of therapeutic intervention. Such clarity in terms of mechanism and intervention can only come from an amalgamation of research from human to animal studies that attempt to mimic the human condition, both of which are discussed in this review. We begin by presenting an outline of our current understanding of the neurobiological basis of fear and anxiety. This outline spans various levels of organization that include the circuitry, molecular pathways, genetic and epigenetic components of fear and anxiety. Using these organizational levels as a scaffold, we then discuss strategies that are currently used to ameliorate these disorders, and forecast future interventions that hold therapeutic promise. Among these newer promising treatments, we include, optogenetic, pharmacological, and extinction-based approaches, as well as lifestyle modifications, with combinatorial treatment regimens of these holding the most promise.

Highlights

► We highlight new therapies for fear and anxiety from the connectome to epigenome. ► Optogenetic approaches will potentially be useful to treat fear and anxiety. ► Drugs that modify the epigenetic landscape hold therapeutic promise. ► Lifestyle interventions (e.g. diet, exercise, meditation) should be considered. ► Combinatorial approaches hold the most promise to alleviate fear and anxiety.

Section snippets

Towards new therapies for disorders of fear and anxiety

By recent estimates, 28% of the U.S. population suffers from some form of anxiety-related disorders during their lifetime [1]. These illnesses result in numerous adverse effects that extend from the impoverishment of the individual's quality of life to the high financial cost incurred to treat them. Understanding the functioning of the nervous system in a healthy and affected state will aid in the development of treatments for these disorders [2]. While the eventual goal of such investigation

Anxiety and fear: operational definitions

While the physical and psychological manifestations of anxiety and fear appear to share commonalities, they are in fact two independent entities that merit operational definitions. Anxiety is characterized as a state of being that arises from general and non-specific stimuli that are perceived as being potentially threatening in the future. This perception often results in an apprehensive mood accompanied by increased arousal and vigilance, which when taken to an extreme, persist for extended

Neural circuitry underlying anxiety and fear

As with any neuropsychiatric disorder, a constellation of brain regions underlie anxiety-like and fear-like states [14••, 15•, 16, 17, 18]. At the core of this is thought to be the ‘extended amydgala’ which includes the central (CeA) and medial (MeA) nuclei of the amygdala and the bed nucleus of the stria terminalis (BNST) (Figure 1). The extended amygdala is responsive to afferent input from the Basolateral Amygdala (BLA), and cortical regions such as the insular cortex. Divisions of the

Brain stimulation and optogenetics

There are many approaches ranging from current therapy and psychopharmacological treatments to future combination and brain-stimulation approaches that hold promise in the treatment of anxiety (Figure 3). Imaging studies have provided evidence to suggest that alteration of brain activity and structure within and between neural circuits plays a critical role in the manifestation of neuropsychiatric disorders [51, 52, 53]. Manipulating this altered brain activity using diverse techniques is

Disclosures

Dr. Ressler is a founding member of Extinction Pharmaceuticals/Therapade Technologies to develop d-cycloserine, a generically available compound, for use to augment the effectiveness of psychotherapy. He has received no equity or income from this relationship within the last three years.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported through NIH (MH071537(KJR), MH096764 (KJR)) as well as the Burroughs Wellcome Fund. Support was received from the NIH/National Center for Research Resources base grant P51RR000165 to Yerkes National Primate Research Center.

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