Psychobiology and molecular genetics of resilience

Abstract

Every individual experiences stressful life events. In some cases acute or chronic stress leads to depression and other psychiatric disorders, but most people are resilient to such effects. Recent research has begun to identify the environmental, genetic, epigenetic and neural mechanisms that underlie resilience, and has shown that resilience is mediated by adaptive changes in several neural circuits involving numerous neurotransmitter and molecular pathways. These changes shape the functioning of the neural circuits that regulate reward, fear, emotion reactivity and social behaviour, which together are thought to mediate successful coping with stress.

Figure 1. Epigenetic mechanisms of stress responsiveness

Female rats show a range of maternal behaviours, from low levels of licking and other types of grooming of their pups to high levels. These differences during early life can give rise to life-long differences in stress responsiveness,. a | Receiving low levels of grooming results in low levels of the transcription factor nerve growth factor-inducible protein A (NGFI-A; also known as EGR1) in the hippocampus, which permits increased methylation and repression of the glucocorticoid receptor (GR) gene in this brain region. Lower levels of GR expression in the hippocampus contribute to several traits in adulthood: higher levels of baseline and post-stress glucocorticoid (corticosterone) secretion, higher levels of anxiety-like behaviour and, in females, lower levels of grooming behaviour towards their own offspring. b | The offspring of high-grooming mothers have higher levels of hippocampal NGFI-A, resulting in less methylation of the GR gene and higher GR expression in the hippocampus. In adulthood this is associated with lower levels of baseline and post-stress corticosterone secretion, low anxiety-like behaviour and, in females, high levels of grooming of offspring.

Figure 2. Neurobiological mechanisms of resilience in a mouse model

In a chronic social defeat paradigm, vulnerable mice show increased firing of ventral tegmental area (VTA) dopamine neurons, which subsequently gives rise to heightened brain-derived neurotrophic factor (BDNF) protein levels in the nucleus accumbens (NAc) and to a range of depression-like behaviours,. Vulnerable mice also showed activation of signalling molecules downstream of the BDNF receptor TRKB, including phosphorylated AKT and extracellular signal regulated kinase 1 and 2 (ERK1/2), indicating increased BDNF signalling. Unsusceptible or resilient mice resist this adverse cascade of events by upregulating several K⁺ channels in the VTA. TRKB.T, truncated TRKB receptor; TRKB.F, full-length TRKB receptor. Figure is modified, with permission, from REF. 41 © (2007) Cell Press.

Figure 3. Neural circuitries of fear and reward

A simple schematic of the key limbic regions in the fear and reward circuitries. These regions are highly interconnected and function as a series of integrated parallel circuits that regulate emotional states. Each is heavily innervated by the brain's monoaminergic systems — noradrenaline (from the locus coeruleus (LC)), dopamine (from the ventral tegmental area (VTA)) and serotonin (from the raphe nuclei (not shown)) — which are thought to modulate the activity of these areas. a | Fear-inducing sensory information is relayed through the thalamus (Thal) to the amygdala (Amy). The amygdala is particularly important for conditioned aspects of learning and memory, as is best studied in fear models. The hippocampus (HP) has a crucial role in declarative memory, but it probably functions more broadly in regulating emotional, including fear, behaviour. b | The nucleus accumbens (NAc) is a key reward region that regulates an individual's responses to natural rewards and mediates the addicting actions of drugs of abuse. The prefrontal cortex (PFC) — which is composed of multiple regions (for example, the dorsolateral PFC, the medial PFC, the orbitofrontal cortex and the anterior cingulate cortex, among others) with distinct but overlapping functions — is sometimes also included in the limbic system and is essential to emotion regulation. PFC regions provide top-down control of emotional responses by acting on both the amygdala and the NAc (a and b). Several regions that are important for fear and reward learning are not shown in the respective circuits; for example, the NAc also regulates responses to fearful stimuli and the hippocampus also regulates responses to rewarding stimuli. The limbic regions depicted are also part of integrated circuits that mediate social responses and behaviour. The functional status of all of these circuits has important implications for resilience to stressful life events. Notably, alterations in one neurotransmitter, neuropeptide or hormone system will affect more than one circuit. Blue lines represent glutamatergic connections; green lines represent noradrenergic connections; red lines represent dopaminergic connections; the orange line represents a GABA (γ-aminobutyric acid)-ergic connection.