Functional Organization of the Cerebral Cortex and Basal Ganglia

National Institute Of Mental Health

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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, NIDA,NIAAA, and NEI, the University of Pittsburgh, University of California San Francisco (UCSF), the University of Pennsylvania, the Max Planck Institute for Neuroscience, Columbia University, , the Allen Institute, and Carnegie Mellon University. Our contribution to these studies was to help with the experimental design, to provide neuroanatomical expertise and support 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. Prior studies with Bryan Hooks (U Pittsburgh) mapped projections from distinct subtypes of neurons across areas of the cerebral cortex to the basal ganglia and thalamus (Hooks et al., 2018). Analysis revealed principles of how connections between cortical and subcortical areas are organized to integrate sensory and motor cortical information. During the past year the organization of cortical and thalamic input to subtypes of inhibitory neurons in motor cortical areas was studied (Okoro et al., 2022 from Bryan Hooks lab). Using transsynaptic rabies tracing and physiologic techniques revealed specific patterns of long range inputs from somatosensory cortical areas and those from thalamic areas to different layers of motor cortex. These findings support models of how information flow through cortical circuits is sculpted by inhibitory neurons to integrate sensory information in motor function. Cortical areas with different functions provide inputs to distinct regions of the striatum. Work with Marc Fuccillo (University of Pennsylvania) demonstrated that anterior and posterior parts of the prelimbic cortex (PL) respectively target anterior and posterior regions of the striatum. Optogenetic imaging and suppression of PL neurons projecting to these two striatal regions had distinct effects on the animals behavior in a value-based choice paradigm. Anterior PL neurons were involved in choices with negative outcomes while posterior PL neurons were involved in choices with positive outcomes. A study with Massimo Scanziani (UCSF) determined distinct functions of neuroanatomical circuits providing visual information from the eye to the visual cortex (Brenner et al., 2023). Visual information passes into brain through multiple pathways that connect either directly through the thalamus to the visual cortex or indirectly through the superior colliculus (the tectum) to the thalamic nuclei that project to the visual cortex. With a transgenic mouse Cre-line that labeled a specific subtype of neurons in the superior colliculus (Gerfen et al., 2013), a genetically defined pathway from the superior colliculus through the thalamus was identified that functions to distinguish self-generated from externally-generated visual motion. A major area of active research is to determine the functional roles of the striatal dopamine D1receptor and D2receptor expressing neurons that give rise to the direct and indirect striatal projection pathways. Ongoing collaborations with Alexandra Nelson (UCSF), Brian Hooks (Pittsburgh University) and Aryn Gittis (Carnegie Mellon University) are studying the distinct roles of these neurons in animal models of Parkinsons Disease and their neuroanatomical connections with cortical neuron subtypes. A study completed during the past year with Da-Ting Lin (NIDA) used a intracerebral fluorescence imaging technique to measure activity in D1r and D2r striatal neurons during ongoing motor behavior (Liang et al, 2022). Results demonstrated that during the learning of motor skill task, both direct (D1r) and indirect (D2r) neurons are active. Direct (D1r) striatal neurons displayed increased activity as the animals skill increased and selective inactivation of these neurons suppressed motor skill learning, whereas indirect (D2r) neurons did not change their pattern of activity and inactivation did not affect motor learning.