Thus, as is apparent below, studies of the effects of stress on PFC in rodent have focused on mPFC. While the PFC is highly evolved in NHPs and humans and mediates particularly complex cognitive processes, it is also highly vulnerable. The PFC has been implicated in multiple brain disorders such as attention deficit disorder, schizophrenia, depression, and

PTSD (Arnsten, 2009a, Drevets et al., 1997b, Gamo and Arnsten, 2011 and Tan et al., 2007), and it is also vulnerable to stress (McEwen and Gianaros, 2011) and normal aging (Morrison and Baxter, 2012), as well as Alzheimer’s disease (Hof and Morrison, 2004 and Morrison and Hof, 1997) in humans. The PFC has also been identified as a cortical MDV3100 region that is

affected by decreased estrogen levels in women (Shanmugan and Epperson, 2012). Monkey studies have highlighted Epigenetics Compound Library the vulnerability of dorsolateral PFC (dlPFC) to stress (Arnsten, 2009b), aging (Morrison and Baxter, 2012 and Wang et al., 2011), and estrogen depletion (Hao et al., 2006, Hao et al., 2007 and Rapp et al., 2003). As will be discussed in detail in this Review, the homologous mPFC is highly vulnerable to stress (Cook and Wellman, 2004, Holmes and Wellman, 2009 and Radley et al., 2004), aging (Bloss et al., 2011), and estrogen depletion (Shansky et al., 2010) in rats. Thus, while PFC clearly is an important target for intervention regarding multiple devastating brain disorders in humans, the animal models faithfully reflect several of its vulnerabilities and can thus provide important mechanistic insights into the unique most capacities and vulnerabilities of this neocortical region that plays such a crucial role in higher cognitive processes. The mPFC has extensive downstream projections to regions as diverse as the amygdala and the brainstem (Sesack et al., 1989), providing a substrate for downstream regulation of autonomic and neuroendocrine balance (Thayer and

Brosschot, 2005), with influences on parasympathetic (Thayer and Sternberg, 2006) and hypothalamo-pituitary adrenal (HPA) activity (Diorio et al., 1993). For HPA activity and autonomic control in rat, dorsal and ventral mPFC have different effects, based on experiments showing that lesions to the dorsal mPFC enhanced restraint stress-induced c-Fos and corticotropin-releasing factor (CRF) mRNA expression in the neurosecretory region of the paraventricular hypothalamus (PVH), whereas ablation of the ventral mPFC decreased stress-induced c-Fos protein and CRF mRNA expression in this compartment but increased c-Fos induction in PVH regions involved in central autonomic control (Radley et al., 2006).