Functional topography of serotonergic systems supports the Deakin/Graeff hypothesis of anxiety and affective disorders

Abstract

Over 20 years ago, Deakin and Graeff hypothesized about the role of different serotonergic pathways in controlling the behavioral and physiologic responses to aversive stimuli, and how compromise of these pathways could lead to specific symptoms of anxiety and affective disorders. A growing body of evidence suggests these serotonergic pathways arise from topographically organized subpopulations of serotonergic neurons located in the dorsal and median raphe nuclei. We argue that serotonergic neurons in the dorsal/caudal parts of the dorsal raphe nucleus project to forebrain limbic regions involved in stress/conflict anxiety-related processes, which may be relevant for anxiety and affective disorders. Serotonergic neurons in the "lateral wings" of the dorsal raphe nucleus provide inhibitory control over structures controlling fight-or-flight responses. Dysfunction of this pathway could be relevant for panic disorder. Finally, serotonergic neurons in the median raphe nucleus, and the developmentally and functionally-related interfascicular part of the dorsal raphe nucleus, give rise to forebrain limbic projections that are involved in tolerance and coping with aversive stimuli, which could be important for affective disorders like depression. Elucidating the mechanisms through which stress activates these topographically and functionally distinct serotonergic pathways, and how dysfunction of these pathways leads to symptoms of neuropsychiatric disorders, may lead to the development of novel approaches to both the prevention and treatment of anxiety and affective disorders.

Dorsal raphe nucleus and harm avoidance: A resting-state investigation

“…Following removal of these component maps, within the DR networks identified we found that HA was significantly correlated with resting activity in the basal amygdala and ventral hippocampus. This is in accordance with the Deakin and Graeff hypothesis, suggesting that serotonergic neurons in the DR project to the basolateral amygdala and ventral hippocampus in the process of mediating conflict and anxiety (Paul & Lowry, 2013). Indeed, it is well-known that the amygdala plays a critical role in emotional regulation and anxiety, and that amygdala dysregulation predisposes an individual to developing anxiety disorders, which are associated with significantly increased HA (Hariri & Whalen, 2011;Pessoa, 2011;Starcevic, Uhlenhuth, Fallon, & Pathak, 1996).…”

Central mechanisms regulating coordinated cardiovascular and respiratory function during stress and arousal

“…For example, locomotion is associated with coordinated cardiovascular and respiratory changes, but the extent to which brain pathways regulating exercise-induced cardiorespiratory responses overlap with those regulating stress-evoked cardiorespiratory responses is not known. Another major general issue concerns the role of noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe, both of which are activated during stress and arousal and have widespread projections to many parts of the brain, including key nuclei involved in cardiovascular and respiratory regulation (7,98,124). Furthermore, the nucleus incertus in the pons and lateral habenula in the midbrain have recently been shown to contain neurons that are strongly activated by stress and which also project very widely throughout the brain (73,130).…”

Different patterns of 5-HT receptor and transporter dysfunction in neuropsychiatric disorders – a comparative analysis of in vivo imaging findings

“…In particular, the Deakin/Graeff theory (Deakin and Graeff, 1991) surmises different pathways controlling behavioral responses to aversive stimuli. Thereby, the dorsal raphe periventricular tract is supposed to inhibit 'fight-or-flight' responses by stimulation of 5-HT 1A R and/ or 5-HT 2A R. Disinhibition of this pathway is believed to result in bouts of sympathetic and behavioral arousal comparable to PD (for review, see Paul and Lowry, 2013). The mesencephalic 5-HT 1 R desensitization observed in the present analysis and the resulting disinhibition, thus, are in line with the hypothesized 5-HT 1A R dysfunction in the dorsal raphe periventricular tract.…”