Modulators in concert for cognition: modulator interactions in the prefrontal cortex

Abstract

Research on the regulation and function of ascending noradrenergic, dopaminergic, serotonergic, and cholinergic systems has focused on the organization and function of individual systems. In contrast, evidence describing co-activation and interactions between multiple neuromodulatory systems has remained scarce. However, commonalities in the anatomical organization of these systems and overlapping evidence concerning the post-synaptic effects of neuromodulators strongly suggest that these systems are recruited in concert; they influence each other and simultaneously modulate their target circuits. Therefore, evidence on the regulatory and functional interactions between these systems is considered essential for revealing the role of neuromodulators. This postulate extends to contemporary neurobiological hypotheses of major neuropsychiatric disorders. These hypotheses have focused largely on aberrations in the integrity or regulation of individual ascending modulatory systems, with little regard for the likely possibility that dysregulation in multiple ascending neuromodulatory systems and their interactions contribute essentially to the symptoms of these disorders. This review will paradigmatically focus on neuromodulator interactions in the PFC and be further constrained by an additional focus on their role in cognitive functions. Recent evidence indicates that individual neuromodulators, in addition to their general state-setting or gating functions, encode specific cognitive operations, further substantiating the importance of research concerning the parallel recruitment of neuromodulator systems and interactions between these systems.

Figure 1

Schematic representation of coronal sections from the macaque monkey PFC illustrating the relative densities of tyrosine hydroxylase (DA), dopamine β-hydroxylase (NE), choline acetyltransferase (ChAT), and serotonin-containing axons. Numbers refer to the cortical areas described by Walker (1940). CS, cingulate sulcus; LO, lateral orbital sulcus; MO, medial orbital sulcus; PS, principal sulcus; and RS, rostral sulcus. This figure was published originally in Lewis et al. (1992) and re-drawn and colorized by Mary L. Brady (Photomicrography & Graphics Specialist, Translational Neuroscience Program, University of Pittsburgh). Reproduced with permission of the author (D.A. Lewis) and Nature Publishing Group (License Number 1676551084929).

Figure 2

The dorsal raphe (DR), locus coeruleus (LC), basal forebrain cholinergic system (BFCS), and the ventral tegmental area (VTA) all send projections to and receive projections from the PFC. These parallel feedback loops provide a mechanism through which serotonergic, noradrenergic, cholinergic, and dopaminergic modulatory systems can directly affect cortical targets and be modulated by descending glutamatergic projections. Feedback to ascending neuromodulatory systems can occur directly from the PFC or indirectly via feedback loops from other modulatory nuclei at the levels of the brainstem, midbrain, and basal forebrain. For example, as shown above, the caudal principal LC sends substantial projections to the caudal, ventromedial, and intrafasicular DR and in return, the caudal DR and ipsilateral wing of the DR sends heavy projections to the mid-ventral and caudal dorsal LC. Ascending noradrenergic and serotonergic projections, along with projections from the VTA innervate the BFCS. In addition to sharing a parallel and closed-loop system organization, 5-HT, NE (NE), DA, and ACh neuromodulator systems exhibit overlapping innervation patterns and terminal fields.