Covariation of Activity in Habenula and Dorsal Raphé Nuclei Following Tryptophan Depletion

Abstract

Abnormal serotonergic function is implicated in the pathogenesis of affective disorders. We induced transient depressive relapses in volunteer patients by rapidly depleting plasma tryptophan, the precursor of serotonin (5-HT), and measured neural activity during different cognitive tasks using positron emission tomography (PET). Neural activity in several 5-HT-related brain areas, e.g., dorsal raphé, habenula, septal region, amygdala, and orbitofrontal cortex, covaried significantly with plasma levels of tryptophan and ratings of depressed mood. Task-specific responses in left amygdala and left anterior cingulate were attenuated by tryptophan depletion. We used these PET data to test the hypothesis that projections from the habenula modulate dorsal raphé activity and that this modulation is enhanced in patients experiencing a profound mood change following serotonergic challenge. A strong linear correlation (r(2) > 0.5) between habenula and raphé activity was observed in subjects with postdepletion ratings >/=10 on a modified Hamilton depression scale, whereas subjects experiencing milder changes in mood had weaker habenula-raphé coupling (r(2) < 0.5). These data support a model of the serotonergic system in which the habenula projection to the raphé represents a convergent feedback pathway that controls the release of 5-HT throughout the brain. In our experiment we were able to engage this system in patients who were sensitive to tryptophan depletion.

Ionic Mechanism of Long-Lasting Discharges of Action Potentials Triggered by Membrane Hyperpolarization in the Medial Lateral Habenula

“…In agreement with the anatomical circuitry, the electrical activity of the habenula has been shown to exert a powerful control over the activity of serotonin cells in the nucleus of dorsal raphe and dopamine cells in the ventral tegmental area and substantia nigra (Matsuda and Fujimura, 1992;Ferraro et al, 1996;Morris et al, 1999;Conley et al, 2002).…”

Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus

“…Indeed, lethargy and lack of motivation are core symptoms of major depressive disorder (American Psychiatric Association, 2013). The LHb, which activates and inactivates the RMTg and VTA, respectively (Hong et al, 2011), is overactive in rat models of depression (Caldecott-Hazard et al, 1988;Shumake et al, 2003;Li et al, 2013) and depressed human patients (Morris et al, 1999;Roiser et al, 2009). Inhibition of the LHb reverses depression-like behaviors in rats (Winter et al, 2011) and the LHb has been targeted with some success in deep brain stimulation to treat treatment-resistant depression in humans (Sartorius et al, 2010;Schneider et al, 2013).…”

Anterior Cingulate and Subgenual Prefrontal Blood Flow Changes Following Tryptophan Depletion in Healthy Males

“…This may reflect multiple depression phenotypes (with differential response to treatments), differences related to underlying disease processes (trait effects), differing symptom severity (state effects), or differences in the tasks performed by subjects during scan acquisition. In MDD, RTD induces significant changes in rCBF and rCMRglc in this depression-related neural network, both associated with RTD-induced mood deterioration (Bremner et al, 1997;Morris et al, 1999;Smith et al, 1999) and apparently independent of mood change (Neumeister et al, 2004). Although there are relative differences in regional and directional findings across these studies, possibly related to differences in methodology, medication status, and severity of RTD-induced mood deterioration, they support the hypothesis that (at least in a significant proportion of patients) the dysfunction in the depressionrelated neural network is 5-HT-related and can be unmasked by transient 5-HT reduction even in the absence of depressive symptoms.…”