Dissecting the Prefrontal Network With Pathway-Selective Manipulation in the Macaque Brain—A Review

Abstract

Macaque monkeys are prime animal models for studying the neural mechanisms of decision-making because of their close kinship with humans. Manipulation of neural activity during decision-making tasks is essential for approaching the causal relationship between the brain and its functions. Conventional manipulation methods used in macaque studies are coarse-grained, and have worked indiscriminately on mutually intertwined neural pathways. To systematically dissect neural circuits responsible for a variety of functions, it is essential to analyze changes in behavior and neural activity through interventions in specific neural pathways. In recent years, an increasing number of studies have applied optogenetics and chemogenetics to achieve fine-grained pathway-selective manipulation in the macaque brain. Here, we review the developments in macaque studies involving pathway-selective operations, with a particular focus on applications to the prefrontal network. Pathway selectivity can be achieved using single viral vector transduction combined with local light stimulation or ligand administration directly into the brain or double-viral vector transduction combined with systemic drug administration. We discuss the advantages and disadvantages of these methods. We also highlight recent technological developments in viral vectors that can effectively infect the macaque brain, as well as the development of methods to deliver photostimulation or ligand drugs to a wide area to effectively manipulate behavior. The development and dissemination of such pathway-selective manipulations of macaque prefrontal networks will enable us to efficiently dissect the neural mechanisms of decision-making and innovate novel treatments for decision-related psychiatric disorders.

Genetic Approaches for Neural Circuits Dissection in Non-human Primates

“…Researchers have faced enormous challenges due to many obstacles, including limited transfection efficiency, inefficient light delivery and readout equipment, severe immune responses, and deficient injection protocols. After continuous improvement, NHP optogenetics has been transformed, fueled by developments in viral transudation efficiency (e.g., AAV2.1), surgical procedures (e.g., the convection-enhanced delivery (CED) method and window implantation), light delivery devices (e.g., the coaxial optrode), and readout approaches (e.g., fMRI and Ca 2+ imaging) [ 43 , 70 , 79 - 83 ]. In the last decade, primates optogenetics have started an era of mesoscopic neuronal circuit neuroanatomy and functional studies with cell-type specificity (e.g., dopamine neurons and Purkinje cells) and pathway selectivity (e.g., FEF to SC and LGN to V1).…”

“…Such studies have focused on face gender discrimination, direction discrimination, decision confidence, value-based learning, working memory, reward prediction, visual perception, saccade movement, and forelimb movements. Most of those studies have been completed in the primary visual system and the frontal system [ 15 , 16 , 27 , 40 , 57 , 68 , 69 , 71 , 72 , 75 - 77 , 83 - 97 ] (Fig. 3 A).…”

Pathway-selective optogenetics reveals the functional anatomy of top–down attentional modulation in the macaque visual cortex

“…In this study, we used pathway-selective optogenetics ( 33 , 35 ) to selectively manipulate the axonal projections from the FEF to visual area MT to determine whether the FEF affects the attentional modulation of firing rates in MT via this direct pathway. In a previous study, we have shown that injection of a viral vector into the FEF leads to the incorporation of opsins into the axonal membrane of FEF neurons projecting to area MT ( 36 ).…”