Review
Special Issue: Cognition in Neuropsychiatric Disorders
Neural circuits underlying the pathophysiology of mood disorders

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Although mood disorders constitute leading causes of disability, until recently little was known about their pathogenesis. The delineation of anatomical networks that support emotional behavior (mainly derived from animal studies) and the development of neuroimaging technologies that allow in vivo characterization of anatomy, physiology, and neurochemistry in human subjects with mood disorders have enabled significant advances towards elucidating the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). In this review, we integrate insights from human and animal studies, which collectively suggest that MDD and BD involve dysfunction within an extended network including the medial prefrontal cortex and anatomically-related limbic, striatal, thalamic and basal forebrain structures.

Section snippets

Animal and human studies of mood disorders

Major depressive disorder (MDD) and bipolar disorder (BD) constitute the first and fifth leading causes of years lived with disability, respectively [1]. Yet, until recently, little was known about their pathogenesis, as these conditions are not associated with gross brain pathology or clear animal models for spontaneous recurrent mood episodes. The development of neuroimaging technologies that allow in vivo characterization of anatomy, physiology, and neurochemistry in human subjects with mood

Cognitive and emotional disturbances in MDD and BD

The clinical phenomenology of major depression implicates brain systems involved in the regulation of mood, anxiety, fear (e.g., panic attacks, phobias and post-traumatic stress syndromes commonly occur co-morbidly with depression), reward processing, attention, motivation, stress responses, social interaction, and neurovegetative function (i.e., sleep, appetite, energy, weight, libido) [1]. In BD, episodes of depression occur alternately with manic or hypomanic episodes, during which mood can

Observations in experimental animals

There is considerable evidence that the amygdala and related medial prefrontal cortical areas are centrally involved in mood disorders, based on imaging and histopathological studies in humans, as well as deep brain stimulation in intractable patients [24]. Converging with this is a body of experimental anatomical evidence from animals, especially monkeys, that there is a connectional network that involves the amygdala and several areas in the mPFC, the adjacent medial edge of the orbital

Anatomy and connectivity

The connections of the amygdala are a good starting point for understanding emotion related circuitry. Experiments in rats, cats, and more recently monkeys have shown that the basal and lateral amygdala have reciprocal connections to the medial prefrontal network and, to a lesser extent, to the orbital network, as well as to related insular and temporal cortical areas, the mediodorsal thalamic nucleus and the ventromedial striatum [30] (Figure 2 and Figure 3). Outputs to hypothalamic and

Anatomy and connectivity

In the 1990s, a series of axonal tracing experiments in macaque monkeys more completely defined the cortical and sub-cortical circuits related to the OMPFC and the amygdala. More specifically, two networks of interconnected regions that also have common connections with other cortical regions were recognized within the OMPFC. These networks have been referred to as [25] (Figure 1).

Recently, a similar analysis of the organization and connections of the lateral PFC (LPFC) has been performed.

Anatomy and connectivity

Substantial outputs exist from the medial prefrontal network to the hypothalamus, PAG, and other visceral control centers [25]. The subgenual cortex provides the heaviest projection, which terminates in both the medial and lateral hypothalamus, and in both dorsolateral and ventrolateral columns of the PAG. The origin of the projection extends beyond the medial prefrontal network to include the rostral superior temporal gyrus and area 9 in the DPFC, both of which are strongly related to the

Anatomy and connectivity

The PFC has specific connections with the striatum and thalamus and several circuits can be identified. The first are the reciprocal thalamo-cortical connections that relay subcortical input to the cortex through principal thalamic nuclei. The well-known cortico-striato-pallido-thalamic loops are closely related to these (Figure 3). The medial prefrontal network, in particular, is connected to both the medial segment of the mediodorsal thalamic nucleus (MDm) and the ventromedial part of the

Implications for neurocircuitry-based models of depression

Within the larger context of the limbic-cortical-striato-pallido-thalamic circuits implicated in the pathophysiology of depression, the functional implications of some limbic-cortical circuits involving the medial prefrontal network merit comment in light of the abundant basic science literature available to guide translational models. The anatomical projections from the medial prefrontal network to the amygdala, hypothalamus, PAG, locus coeruleus, raphe, and brainstem autonomic nuclei play

Concluding remarks

The experimental observations described here provide an indication of the circuitry and structures that are involved in mood disorders and related conditions. The description is not yet complete and there are many important details that have yet to be worked out, but important foci such as the subgenual prefrontal cortex and the amygdala can be identified and their relationships understood. The system is complex and, although there are many suggestions, it is not possible yet to identify the

Acknowledgements

J.L.P. is supported by grant R01 MH070941 from the USPHS/NIMH and W.C.D. by funds from The William K. Warren Foundation.

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