Muscarinic M1 receptor overstimulation disrupts working memory activity for rules in primate prefrontal cortex. Vijayraghavan S, Major AJ, Everling S (2017) Neuron pii: S0896-6273(18)30425-2.
In vivo manganese tract tracing of frontal eye fields in rhesus macaques with ultra-high field MRI: comparison with DWI tractography.
Schaeffer DJ, Johnston KD, Gilbert KM, Gati JS, Menon RS, Everling S (2018) Neuroimage 181:211-218
The common marmoset (Callithrix jacchus) has garnered recent attention as a potentially powerful preclinical model and complement to other canonical mammalian models of human brain diseases (e.g., rodents and Old World non-human primates). With a granular frontal cortex and the advent of transgenic modifications, marmosets are well positioned to serve as neuropsychiatric models of prefrontal cortex dysfunction. A critical step in the development of marmosets for such models is to characterize functional network topologies of frontal cortex in healthy, normally functioning marmosets. Here, we sought to characterize the intrinsic functional connectivity of anterior cingulate cortex (ACC) in marmosets using resting state functional magnetic resonance imaging (RS-fMRI). Seven lightly anesthetized marmosets were imaged at ultra-high field (9.4 T) and hierarchical clustering was employed to extract functional clusters of ACC from the RS-fMRI data. The data demonstrated three functionally discrete clusters within ACC. The functional connectivity between these clusters with the rest of the brain was also found to be distinct, supporting the hypothesis that ACC subregions serve different circuits and their concomitant functions. In a separate seed-based analysis, we also sought to delineate finer-grained patterns of ACC connectivity between marmoset primary motor area 4 ab and putative eye movement areas (8aD and 8 aV). This analysis demonstrated distinct patterns of ACC functional connectivity between motor and eye movement regions that overlapped well with what has been shown in humans and macaques. Overall, these results demonstrate that marmosets have a network topology of ACC that resembles that of Old World primates, giving further credence to the use of marmosets for preclinical studies of intractable human brain diseases.
Acetylcholine release in the prefrontal cortex (PFC), acting through muscarinic receptors, has an essential role in regulating flexible behavior and working memory (WM). General muscarinic receptor blockade disrupts PFC WM representations, while selective stimulation of muscarinic receptor subtypes is of great interest for the treatment of cognitive dysfunction in Alzheimer's disease. Here, we tested selective stimulation and blockade of muscarinic M1 receptors (M1Rs) in macaque PFC, during performance of a cognitive control task in which rules maintained in WM specified saccadic responses. We hypothesized that M1R blockade and stimulation would disrupt and enhance rule representation in WM, respectively. Unexpectedly, M1R blockade did not consistently affect PFC neuronal rule selectivity. Moreover, M1R stimulation suppressed PFC activity, and at higher doses, degraded rule representations. Our results suggest that, in primates, the deleterious effects of general muscarinic blockade on PFC WM activity are not mediated by M1Rs, while their overstimulation deteriorates PFC rule maintenance.
The saccadic eye movement system has emerged as a valuable model for studying neural circuitry related to flexible control of behavior. Although connections of the saccadic circuitry are well documented via histochemical tracers, these methods require fixed tissue and thus cannot provide longitudinal assessments of connectivity. To circumvent this, diffusion weighted imaging (DWI) is often used as a proxy for connectivity in vivo, allowing for
the tracing of connections longitudinally and noninvasively. DWI, however, has certain limitations in its ability to estimate the paths of fiber tracts. Here, we demonstrate the use of manganese, in an animal model, as an MRI-based in vivo labeling technique for saccadic circuitry that allows for direct tract tracing without the need to sacrifice the animal. Manganese is a strong paramagnetic contrast agent used for T1-relaxation enhancement in MRI. Here, we locally injected MnCl2 into the frontal eye fields (FEF), a key saccadic node, of two male rhesus
macaques and collected ultra-high field MRI data at 7T (T1, DWI). The results demonstrate that MnCl2-traced FEF connections parallel those established by histochemical tracing (albeit at a lower spatial resolution) and suggest that DWI underestimates FEF connectivity, likely due to crossing fibers and small tract size. These results highlight the lack of DWI sensitivity for tracing subcortical FEF fibers, but also suggest MnCl2-based tracing as a powerful alternative for assessing these connections in vivo.