The inverted U- alterations in PFC function based on arousal state

Understanding how neuromodulators influence dlPFC circuits helps to explain how higher cognition is altered by our state of arousal. In deep sleep we may be unconscious due to the absence of acetylcholine stimulation of nic-a7R which is permissive for NMDA actions. When we are awake, cholinergic stimulation of nic-a7R allows networks to connect. Moderate levels of norepinephrine release in response to interesting events stimulates a2A-AR, which strengthens preferred connections and promotes PFC cognitive abilities. Dopamine is also released to salient events, which gates out nonpreferred network inputs through stimulation of D1R. Low levels of dopamine D1R sculpting may be optimal for creative thinking when a broad range of inputs are needed, while moderate levels of D1R stimulation may be optimal for tasks requiring precise focus. In contrast, high levels of norepinephrine and dopamine release during stress suppress neuronal firing and impair prefrontal function through a a1R and D1R, respectively.

If you are interested: Arnsten AFT, Wang MJ, Paspalas CD (2012) Neuromodulation of thought: Flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76: 223-239.

NE has higher affinity for a2A-AR than for a1-AR. Thus, during times when we are alert, interested and feel safe, moderate levels of NE release engage high affinity a2A-AR that strengthens PFC delay-related firing for the neurons’ preferred direction and improves PFC function. In contrast, high levels of NE release during stress exposure engage lower affinity a1-AR, which suppress PFC neuronal firing and impair cognition. This pattern is opposite to that in the amygdala, where a1-AR improves and a2A-AR impairs the emotional responding of the amygdala. Thus, low vs. high levels of NE release can serve as a switch to determine which brain system controls our behavior: top-down control by the PFC (a2A-AR), or unconscious emotional responses of the amygdala (a1-AR).

Stimulation of DAD1R produces an inverted-U dose response on both PFC neuronal firing and on cognitive performance. We first discovered the D1 inverted-U when examining the effects of stress exposure on dlPFC cognitive function. D1R were thought to have universally beneficial effects on PFC function, but the detrimental actions of high levels of DA release during stress revealed the impairing actions of excessive D1R stimulation. Physiological studies have revealed that low dose D1R blockade produces noisy firing patterns, while optimal levels of D1R stimulation gate out noise but leave “signals” intact. High doses of D1R stimulation suppress all cell firing.

If you are interested: Vijayraghavan et al (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 10: 376-84.

Dopamine actually has a delicate pattern of innervation of the dlPFC, while more medial areas of PFC are more dense. DA likely has a wide range of actions on PFC neurons, characterized here schematically by changes in memory fields. Total loss of D1R stimulation markedly reduces firing, while more subtle decreases lead to noisy responding. Optimal levels reduce noise and focus neuronal memory fields,, while still higher levels suppress all firing.

We have hypothesized that D1R stimulation gates out all nonpreferred inputs, e.g. nonpreferred spatial directions as well as nonspatial inputs. In contrast, a2-AR strengthens preferred inputs. Thus, neuromodulators help to shape and sculpt the contents of working memory.