Biology Reference
In-Depth Information
Pathways between the amygdala and the mPFC are also involved in the response to
stress. Acute stress blocks LTP at inputs from the basolateral amygdala to the prelimbic
mPFC (Maroun and Richter-Levin 2003). Conversely, stress reduces LTD (evoked by low
frequency stimulation) and facilitates LTP at inputs from the prelimbic and infralimbic mPFC
to the basolateral amygdala (Maroun 2006). Thus it appears that higher order processing in
the mPFC is impaired during stress to allow more autonomic-type responses, mediated by
plasticity in the amygdala. Functionally, it is now widely viewed that phobias and post-
traumatic stress disorder result from an inability to extinguish fear memories. For example,
patients with post-traumatic stress disorder have reduced activity in the mPFC during recall of
the traumatic event (Bremner et al. 1999), but increases in mPFC activity following
successful therapeutic treatment (Fernandez et al. 2001). Consistent with this, stress can
impair extinction (Miracle et al. 2006), and has been shown to increase dendritic branching
and spine numbers in the basolateral amygdala (Vyas et al. 2002; Mitra et al. 2005; Vyas et
al. 2006), but to decrease dendritic branching in the infralimbic PFC (Izquierdo et al. 2006).
(c) Depression
Evidence from post-mortem studies and fMRI has suggested that antidepressants such as
fluoxetine (“Prozac”) act by enhancing neurogenesis and structural plasticity, leading to the
“neurotoxic hypothesis” (Manji and Duman 2001; Santarelli et al. 2003; Fossati et al. 2004).
This hypothesis states that depression results from an impairment in establishing new
neuronal adaptations, synaptic connections and synaptic plasticity, in addition to changes in
neurotransmitter concentrations and receptor levels. Some of this “neurotoxicity” is likely to
reside in the mPFC and in connections between the hippocampus and mPFC. For example,
prolonged depression is associated with atrophy of the prefrontal cortex, particularly dendritic
atrophy in layer 2/3 (Ongur et al. 1998; Cook and Wellman 2004; Fossati et al. 2004; Radley
et al. 2004), in addition to atrophy of the hippocampus (Bremner et al. 2000). A reduction in
metabolic activity in the mPFC (Dolan et al. 1994; Drevets et al. 1997), in association with
cognitive dysfunction (Dolan et al. 1992), is also seen during depression, and can be reversed
by treatment by selective serotonin reuptake inhibitors (SSRI; Kennedy et al. 2001).
Furthermore, chronic antidepressant treatment evokes increases in the expression of
molecules associated with synaptic plasticity in the mPFC, namely CREB, synaptophysin and
the polysialylated form of nerve cell adhesion molecule (PSA-NCAM; Tiraboschi et al. 2004;
Laifenfeld et al. 2005; Sairanen et al. 2007; Varea et al. 2007a; Varea et al. 2007b). Finally,
and consistent with the notion that connections between the hippocampus and the mPFC may
be impaired in depression, treatment with an SSRI also enhances synaptic transmission and
LTP at hippocampal-mPFC synapses in vivo (Ohashi et al. 2002).
(v) Drugs of abuse
Many drugs of abuse have been shown to exert actions in the mPFC. For example, many
drugs cause cognitive impairments (Moghaddam et al. 1997; Bisagno et al. 2002; Nordahl et
al. 2003). The psychotomimetic drugs ketamine and phencyclidine have been shown to
increase glutamate and dopamine levels in the rat mPFC, which is associated with an
impairment of working memory (Nishijima et al. 1994; Moghaddam et al. 1997; Adams and
