The Mesolimbic Reward Pathways in Depression

The authors of this article [Nestler and Carlezon, 2006: (http://www3.utsouthwestern.edu/contecenter/refs/Nestler2.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/16566899)] discuss the potentially-important roles that dysregulations of the mesolimbic and mesocortical, dopaminergic pathways may play in the etiology of major depression. Carlezon is a researcher at Harvard Medical School and has contributed to a lot of really interesting research, such as the research showing antidepressant effects of uridine or cytidine in animal models of depression [Carlezon et al., 2002; Carlezon et al., 2005, both cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/02/potential-psychiatric-pitfalls-in.html)]. Nestler and Carlezon (2006) note that the tendency has been to focus on changes in the hippocampus or prefrontal cortex in depression, etc. It's stunning to me that someone had to write an article like this. Of course one would expect, in my opinion, the mesolimbic reward pathways to be dysregulated in people with depression. It's also noteworthy that some hippocampal neurons project to the prefrontal cortex and are thought to be important in the regulation of dopaminergically-mediated working memory performance. For example, Seamans et al. (1998) [Seamans et al., 1998: (http://www.jneurosci.org/cgi/content/full/18/4/1613)(http://www.ncbi.nlm.nih.gov/pubmed/9454866?dopt=Abstract)] discussed the way in which dopaminergic neurons, originating in either the ventral tegmental area (VTA) or nucleus accumbens or other sites in the striatum [Carr and Sesack, 2000, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/03/adenosine-and-guanosine-in-animal.html)], project to and form synapses with GABAergic interneurons in the prefrontal cortex and are thought, via the activation of D1 dopamine receptors on those GABAergic interneurons, to exert a largely inhibitory influence on the burst firing patterns of glutamatergic pyramidal neurons that originate in the prefrontal cortex and provide monosynaptic inputs back to the dopaminergic neurons in the VTA, in the midbrain. The "regulatory" effects of glutamatergic inputs, originating in the prefrontal cortex, to the VTA are important for maintaining the normal burst firing patterns of VTA neurons, and the burst firing patterns of dopaminergic neurons in the VTA are crucially important for processes such as reward-based learning, cognitive functioning, and motivation, etc. Dopaminergic neurons in the VTA can also produce excitatory or inhibitory effects on glutamatergic neurons in the prefrontal cortex by modifying the excitatory or inhibitory effects of hippocampal neurons that provide inputs to the same classes of GABAergic interneurons that regulate the layer V glutamatergic neurons that project back to the VTA. In any case, those are some ways the reward pathways interact with the hippocampus and prefrontal cortex, and many of those interactions would, in my opinion, be relevant to an understanding of dysregulations of the reward pathways in people with major depression.