Stress weakens prefrontal networks: molecular insults to higher cognition

Abstract

A variety of cognitive disorders are worsened by stress exposure and involve dysfunction of the newly evolved prefrontal cortex (PFC). Exposure to acute, uncontrollable stress increases catecholamine release in PFC, reducing neuronal firing and impairing cognitive abilities. High levels of noradrenergic α1-adrenoceptor and dopaminergic D1 receptor stimulation activate feedforward calcium-protein kinase C and cyclic AMP-protein kinase A signaling, which open potassium channels to weaken synaptic efficacy in spines. In contrast, high levels of catecholamines strengthen the primary sensory cortices, amygdala and striatum, rapidly flipping the brain from reflective to reflexive control of behavior. These mechanisms are exaggerated by chronic stress exposure, where architectural changes lead to persistent loss of PFC function. Understanding these mechanisms has led to the successful translation of prazosin and guanfacine for treating stress-related disorders. Dysregulation of stress signaling pathways by genetic insults likely contributes to PFC deficits in schizophrenia, while age-related insults initiate interacting vicious cycles that increase vulnerability to Alzheimer's degeneration.

Figure 1

Changes in brain systems controlling behavior under conditions of alert safety versus uncontrollable stress. (a) Under conditions when a subject feels alert, safe and interested, phasic release of catecholamines strengthens the higher cognitive functioning of the PFC, thus allowing top-down regulation of thought, action and emotion. In primates, the PFC is topographically organized, with the dorsal and lateral surfaces mediating attention, thought and action while the ventral and medial aspects mediate emotion. The anatomical projections of these areas reflect these specializations. (b) During stress exposure, high levels of catecholamines take the PFC ‘off-line’ while strengthening the functions of more primitive circuits—for example, the conditioned emotional responses of the amygdala and the habitual actions of the basal ganglia. The amygdala activates brainstem stress systems, which in turn activate the sympathetic nervous system.

Figure 2

The cellular basis of working memory, as discovered by Goldman-Rakic. (a) The oculomotor delayed response (ODR) task. A monkey fixates on a central spot while a cue is briefly lit at one of eight locations. The monkey must remember that location over a delay period while maintaining fixation. At the end of the delay, the fixation point is extinguished and the monkey can move its eyes to the remembered location for juice reward. The cue location constantly changes over hundreds of trials, requiring the constant updating of working memory. (b) The physiology and microcircuitry of the primate dlPFC. Delay cells maintain persistent firing across the delay period for their preferred location, but not other locations. The persistent firing is generated by the recurrent excitation of pyramidal cells with shared preferred directions, likely receiving their information from area 7 of the parietal association cortex. These pyramidal cells excite each other via NMDAR NR2B synapses on spines; there are only subtle influences of AMPARs. The spatial tuning of delay cells is enhanced via lateral inhibition from GABA (G) interneurons. Delay-cell microcircuits reside in deep layer III and possibly superficial layer V. Delay cells are modulated by dopamine actions at D1R but not D2R. In contrast, response cells are modulated by D2R but not D1R and likely reside in layer V. Perisaccadic response cells fire immediately before the motor response and likely convey orders to the motor system, while postsaccadic response cells convey feedback (corollary discharge) about the response. Some response cells show both pre- and postsaccadic firing; that is, both motor and feedback characteristics. Postsaccadic response cell firing relies on AMPAR as well as NMDAR stimulation. Response cells are what are most common in rodent PFC, which has a very large layer V.

Figure 3

Dynamic network connectivity (DNC) in the primate dlPFC. Layer III NMDAR synapses on spines in the primate dlPFC are powerfully modulated by the arousal systems (acetylcholine (ACh), norepinephrine, dopamine). ACh has permissive effects on NMDAR opening via nicotinic α7 receptors (nic-α7R) in the synapse. Feedforward Ca²⁺–cAMP signaling, as driven by stress exposure, can rapidly weaken synaptic efficacy and network connectivity by opening K⁺ channels (HCN, KCNQ) near the synapse and in the spine neck (red). Conversely, inhibition of feedforward Ca²⁺–cAMP signaling strengthens connections (green). The ultrastructural locations of α1-AR and β1-AR in primate dlPFC are not yet known. Asterisk indicates the spine apparatus, the extension of the smooth endoplasmic reticulum into the spine. AC, adenylyl cyclase.

Figure 4

Hypothetical interactions between the intracellular signaling pathways activated by stress exposure and pathways that regulate actin dynamics and inflammation. Stress signaling pathways are shown in red, regulatory pathways and mechanisms that strengthen connectivity are shown in green. Inflammatory pathways are shown in purple; calcium-related signaling events are shown in yellow; Rac1 constitutive activation by PKA is shown in gold; REDD1 inhibition of mTor signaling is shown in pink. Note that the regulation of actin is often studied in cultured neurons and rarely in PFC neurons. Thus, future research will be needed to see stress signaling events alter spine number in PFC pyramidal cells through activation of these pathways.

Figure 5

The multiple, interacting, feedforward vicious cycles that may be disinhibited in the aging dlPFC, contributing to increased vulnerability to degeneration. Red: stress activates feedforward Ca²⁺–cAMP signaling pathways near the glutamate NMDAR synapses on spines. In the young adult dlPFC, the phosphodiesterase PDE4A is anchored by DISC1 next to the spine apparatus (*), an extension of the smooth endoplasmic reticulum (SER), critically positioned to regulate feedforward Ca²⁺–cAMP signaling in dlPFC spines. PDE4A is lost from spines with advancing age, dysregulating Ca²⁺–cAMP signaling and increasing the activation of kinases (for example, PKA and calcium/calmodulin-dependent kinase II (CaMKII)) that phosphorylate tau. IP₃R, inositol-1,4,5-trisphosphate receptor. Brown: pTau aggregates over the spine apparatus, at glutamatergic synapses, and over microtubules in dendrites and traffics in vesicles between neurons. The aggregation of pTau on microtubules in dendrites likely interferes with intracellular trafficking, including the trafficking of APP, the precursor to Aβ. Magenta: APP is cleaved to Aβ when it is trapped in endosomes that contain β-secretase (BACE)—for example, when there is interference with APP endosomal trafficking. Indeed, the increased risk of Alzheimer’s disease conferred by the apoE4 variant is thought to involve increased localization of APP into endosomes. The aggregation of pTau on microtubules may similarly trap APP-containing endosomes and lead to the increased generation of Aβ oligomers. The generation of Aβ oligomers can drive additional vicious cycles by stimulating mGluR5 (ref. 147). mGluR5 are localized near the synapse on spines in dlPFC, positioned to activate feedforward Ca²⁺–cAMP signaling and thus drive more tau phosphorylation. Purple: Aβ fibrils drive inflammation, which can unanchor residual PDE4A and further disinhibit stress signaling pathways. Orange: increased stress signaling may also dysregulate mitochondrial function, as PKA can phosphorylate cyclooxygenase IV (COX_IV) to increase reactive oxygen species (ROS), which also increase tau phosphorylation and Aβ production, leading to additional mitochondrial dysfunction. Thus, dysregulation of stress signaling pathways in the dlPFC with advancing age may contribute to many deleterious molecular events that increase vulnerability to degeneration. Alzheimer’s disease pathology may begin anywhere along these pathways (for example, genetic alterations in APP processing or environmental stressors promoting pTau) and, by driving these interacting cycles, lead to the same degenerative phenotype.