Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 8, 53
eCollection

New Perspectives on Catecholaminergic Regulation of Executive Circuits: Evidence for Independent Modulation of Prefrontal Functions by Midbrain Dopaminergic and Noradrenergic Neurons

Affiliations
Review

New Perspectives on Catecholaminergic Regulation of Executive Circuits: Evidence for Independent Modulation of Prefrontal Functions by Midbrain Dopaminergic and Noradrenergic Neurons

Daniel J Chandler et al. Front Neural Circuits.

Abstract

Cognitive functions associated with prefrontal cortex (PFC), such as working memory and attention, are strongly influenced by catecholamine [dopamine (DA) and norepinephrine (NE)] release. Midbrain dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in the locus coeruleus are major sources of DA and NE to the PFC. It is traditionally believed that DA and NE neurons are homogeneous with highly divergent axons innervating multiple terminal fields and once released, DA and NE individually or complementarily modulate the prefrontal functions and other brain regions. However, recent studies indicate that both DA and NE neurons in the mammalian brain are heterogeneous with a great degree of diversity, including their developmental lineages, molecular phenotypes, projection targets, afferent inputs, synaptic connectivity, physiological properties, and behavioral functions. These diverse characteristics could potentially endow DA and NE neurons with distinct roles in executive function, and alterations in their responses to genetic and epigenetic risk factors during development may contribute to distinct phenotypic and functional changes in disease states. In this review of recent literature, we discuss how these advances in DA and NE neurons change our thinking of catecholamine influences in cognitive functions in the brain, especially functions related to PFC. We review how the projection-target specific populations of neurons in these two systems execute their functions in both normal and abnormal conditions. Additionally, we explore what open questions remain and suggest where future research needs to move in order to provide a novel insight into the cause of neuropsychiatric disorders related to DA and NE systems.

Keywords: catecholamine; dopamine; executive function; norepinephrine; prefrontal cortex.

Figures

FIGURE 1
FIGURE 1
Ventral tegmental area contains functionally heterogeneous subsets of DA neurons. Lammel et al. (2012) showed that DA cells in VTA which receive input from laterodorsal tegmentum (LDT) selectively project to NAc, and their activation drives conditioned place preference. DA cells in VTA which receive input from lateral habenula (LHb) neurons, on the other hand, project selectively to PFC, and their activation promotes conditioned place aversion.
FIGURE 2
FIGURE 2
Distinct brain regions are differentially innervated by noradrenergic neurons in multiple brainstem nuclei. Recent findings from our laboratory (Chandler and Waterhouse, 2012; Agster et al., 2013; Chandler et al., 2013) show that individual LC neurons innervate multiple functionally distinct cortical terminal fields, and that the highest density of NE varicosities in the brain occurs in PFC. A recent finding by Robertson et al. (2013) also challenged the longstanding notion that LC is the sole source of NE to cortex by demonstrating the existence of NE-containing fibers in insular cortex derived from a rhombomere distinct from that in which LC develops, suggesting that this region has privileged access to autonomic and visceral information while the rest of the cortical mantle does not.
FIGURE 3
FIGURE 3
entral tegmental area and LC may work together to guide behavior under different circumstances. (A) During performance in a behavioral task in which an animal is successfully retrieving reward, reciprocal connections between VTA and LC may facilitate elevated output from these nuclei, driving release of DA and NE in PFC to promote working memory, attention, and discrimination of specific stimuli that predict reward. These behavioral operations could collectively contribute to the repetition of that behavior until reward is retrieved. (B) When a previously successful behavioral strategy loses its relevance, NAc may signal to VTA that an expected reward has not occurred. Changes in VTA output could then alter LC output, collectively changing the level of DA and NE release in PFC to diminish working memory and discrimination of specific stimuli, instead allowing the animal to explore new behavioral strategies on the basis of detecting previously irrelevant stimuli.
FIGURE 4
FIGURE 4
Ventral tegmental area and LC neurons have distinct targets but their efferent fibers converge in PFC. In the rodent brain, LC projects heavily to the entire cortical mantle, including PFC and primary sensory and motor areas, but not to the striatum or NAc (Berridge and Waterhouse, 2003). VTA on the other hand innervates NAc and PFC, but provides only sparse innervations to more posterior cortical areas (Berger et al., 1991). Therefore, during periods of arousal and vigilance, when LC and VTA discharge is elevated, DA will be released in NAc, LC will be released in posterior cortical areas, and both catecholamines will be released in PFC. This may be beneficial during behavioral tasks which require sustained attention, as DA in NAc (green) will facilitate reward, NE in cortex (red) will alter the signal to noise ratio of pyramidal neurons to optomize them to specific stimuli, and both catecholamines in PFC (yellow) will work synergistically to facilitate working memory and attention to relevant stimuli.

Similar articles

See all similar articles

Cited by 25 articles

See all "Cited by" articles

References

    1. Agster K. L., Mejias-Aponte C. A., Clark B. D., Waterhouse B. D. (2013). Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex. J. Comp. Neurol. 521 2195–2207 10.1002/cne.23270 - DOI - PMC - PubMed
    1. Arnsten A. F. (2000). Through the looking glass: differential noradenergic modulation of prefrontal cortical function. Neural Plast. 7 133–146 10.1155/NP.2000.133 - DOI - PMC - PubMed
    1. Arnsten A. F. (2007). Catecholamine and second messenger influences on prefrontal cortical networks of “representational knowledge”: a rational bridge between genetics and the symptoms of mental illness. Cereb. Cortex 17(Suppl. 1) i6–i15 10.1093/cercor/bhm033 - DOI - PubMed
    1. Arnsten A. F. (2009). Stress signalling pathways that impair prefrontal cortex structure and function. Nat. Rev. Neurosci. 10 410–422 10.1038/nrn2648 - DOI - PMC - PubMed
    1. Arnsten A. F., Dudley A. G. (2005). Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder. Behav. Brain Funct. 1:2 10.1186/1744-9081-1-2 - DOI - PMC - PubMed

Publication types

Feedback