Functional Organization of the Cerebral Cortex and Basal Ganglia

National Institute Of Mental Health

Investigators

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Abstract

Advances in molecular genetic techniques are revealing new details of the neuroanatomical organization of brain circuitry and the functional role of these circuits in behavior. Engineered viral vector constructs have been developed to label axonal projections of targeted neurons with unprecedented clarity, while others allow for retrograde trans-synaptic labeling of neurons providing inputs or anterograde trans-synaptic labeling of post-synaptic targets of axonal projections. These approaches provide new insights into the functional organization of neural circuits. For example, optogenetic studies have demonstrated the ability to functionally manipulate specific neural pathways to determine their role in behaviors including fear memory, anxiety, feeding, and movement. The analytic potential of these approaches is enhanced by the ability to target specific neuron populations, which are defined components of neural circuits. In recent years as part of the GENSAT project we characterized BAC-Cre driver lines that allow for targeting components of the neural circuits of the cerebral cortex and basal ganglia (Gerfen et al., 2013). These BAC-Cre lines are widely used in research laboratories around the world, being used in over 300 publications per year in studies to determine the function of specific neuronal brain circuits. Our work focuses on the organization of neural circuits responsible for integrating different modes of sensory and experiential information that is utilized in the planning and execution of behavior. To do this we use viral vectors that label the axons of specific cortical neuron subtypes in GENSAT BAC-Cre mouse lines. To analyze these complex patterns of connectivity we developed an efficient process for reconstructing the images through the whole mouse brain using the NIH ImageJ program (Paletzki and Gerfen, 2015). These fully reconstructed whole mouse brain image sets displaying the axonal projections of specific neuron subtypes in multiple cortical areas are registered to a common mouse brain atlas. The ability to register patterns of axonal projections obtained from many brains provides the ability to analyze the complex organization of the neural circuits integrating information between functional cortical areas and how it is transmitted to subcortical circuits responsible for behavior (Eastwood et al., 2019). We are currently working with Ted Usdin (NIMH) to use techniques to clear whole mouse brains combined with light-sheet microscopy to image and analyze neural circuits. In the past year we collaborated with investigators in NIMH, NIAAA, and NEI, at Duke University, Northwestern University, Columbia University, Baylor College of Medicine, the Max Planck Institute for Neuroscience, University of California San Francisco, the Allen Institute, Carnegie Mellon University and the University of Pittsburgh. Our contribution to these studies was to provide neuroanatomical expertise in imaging and analyzing neural circuits to determine the relationship between the organization of information transfer between sensory, motor and association cortical areas and the planning and initiation of movements. During this year neuroanatomical techniques were developed to analyze the functional organization of the relationship between the cerebral cortex, basal ganglia and subcortical circuits including the amygdala, thalamus and midbrain. Soohyun Lee's lab in NIMH is working out the fine details of how local circuits of GABAergic cortical neurons affect the activity of pyramidal neurons in the barrel field of the cerebral cortex. Their study demonstrates that long range inputs from different cortical and subcortical areas differentially and selectively synapse on distinct subtypes of somatostatin, parvalbumin and VIP interneurons (Naskar et al., 2021). These findings were obtained using techniques we developed to analyze whole brain mapping of neuroanatomical circuits. Collabortions with Nuo LI (Baylor College of Medicine) and Hidehiko Inagaki (Max Planck Institute) are studying specific neuroanatomical circuits connecting premotor cortical areas, the striatum and basal ganglia output circuits connecting the thalamus, superior colliculus and midbrain motor area involved in sensory triggers, preparatory activity, action and perceptual selection preceding movement initiation. In a study published this past year, movement initiation in response to an auditory cue was demonstrated to originate in a midbrain locomotor area that generates activity in ascending connections connected through the thalamus to cortical premotor areas (Inagaki et al., 2022). This work establishes neural circuits directly from areas receiving sensory information that inform the subject of their situation with brain circuits that encode the planning and responses to different situations. In addition to specific connections between neuron subtypes within and between different brain areas mechanisms involved in neuronal responses to synaptic input is critical to understanding how brain circuits are involved in behavior. A longstanding interest in our lab has been to understand the effects of dopamine and acetylcholine on different subtypes of neurons in the striatum. Dopamine has opponent affects on the two main pathways of the basal ganglia due to the segregation of the D1 and D2 receptors respectively to the direct and indirect pathway striatal neurons (Gerfen et al., 1990). The D1 receptor couples through the Gs (stimulatory) protein to engage signaling pathways that effect direct pathway neuron functions. Prior work from our lab demonstrated differences between the D1r-direct pathway neurons in the dorsal and ventral striatum in the coupling through the D1r to downstream signaling systems involving activation of the kinase ERK1/2 (Gerfen et al., 2002, 2008). Differences were most apparent in animal models of Parkinsons Disease and in response to psychostimulants such as cocaine. Recent work in the Eiden lab has made significant advances in understanding these differences. Prior work had identified a novel protein, NCS-Rapgef2, as critical to coupling D1r to activation of ERK1/2 (Emery et al., 2012). In a study of cocaines behavioral effects, a new model of ERK activation in D1-dopaminoceptive neurons was proposed. Signaling through the D1r in striatal neurons had been thought to mediated exclusively through PKA coupled to cAMP. However, our findings demonstrated that cAMP coupling to RapGef2 to activate ERK is independent of PKA. This suggests that D1r signaling pathways coupling to PKA and ERK occur through distinct parallel pathways that are differentially regulated to effect changes in gene regulation responsible for long term plasticity affecting behavior. This work was extended to demonstrate that D1 coupled PKA and RapGef2 signaling pathways differently affect different behaviors (Jiang et al., 2020). Nicole Calakos at Duke University developed a technique to visualize neuron activity related to the integrated stress response (ISR). Using this approach we found that dopamine signaling in striatal cholinergic neurons engages the ISR during skill learning (Helseth et al., 2021). In ongoing work with Mario Penzos Unit (NIMH) neuroanatomical connections of two subtypes of neurons in the paraventricular nucleus of the thalamus, those expressing the D2 dopamine receptor and those that do not, demonstrate differences in their projections to different prefrontal cortical areas, the shell and core of the nucleus accumbens and to the basolateral amygdala. The Penzo Unit is studying differences in the behavioral affects mediated by such connections.