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, NIA, the University of Pittsburgh, University of California San Francisco (UCSF), University of Southern California (USC), the Max Planck Institute for Neuroscience, 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. With NIMH IRP scientists, Ana Inacio and Soohyun Lee, an innovative technique was used to identify individual neurons in somatosensory cortex distinguished by the relationship of physiologic activity to different behavioral states and to map their brain wide synaptic inputs. Use of rabies virus has been used for some time to take advantage of the ability of the virus to be transported across synapses to neurons that provide synaptic input to infected neurons, as this allows the virus to travel through multiple synapses from the periphery into the brain. Use of genetically altered rabies allows viral infection of specific neurons in the brain to map neurons throughout the brain that provide synaptic input to those neurons, typically a group of neurons. In this study, an innovative technique was used in which the rabies virus was injected into a single neuron, to allow for mapping of inputs to individual neurons. Brain-wide mapping demonstrated that while individual somatosensory cortical neurons whose activity was correlated with different behavioral states receive inputs from the same brain areas, there are significant differences in the relative numbers of inputs from motor cortex or thalamus. This demonstrates preconfigured network dynamics in motor circuits associated with behavioral state. 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. 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. During the past year, studies of the bilateral projections from frontal, sensory and motor areas were analyzed to quantify differences in the strength and targeting of ipsilateral and contralateral to the basal ganglia, which is involved in movement behavior. Results show that frontal areas involved in motor planning provide more robust bilateral projections than those from sensory and motor cortical areas. This is consistent with sensory and motor cortex involved in sensation and movement of the contralateral body while the frontal cortex has a role in unifying activity for motor planning and decision making. Our pioneering work over 30 years ago established that stimulatory D1- and inhibitory D2-dopamine receptors are segregated respectively in the neurons that give rise to the direct and indirect striatal projection pathways (Gerfen et al., 1990). This organization provides the underlying basis of the movement disorder in Parkinson’s disease. Activity in the direct and indirect striatal pathways respectively promote and suppress motor behavior. In Parkinson’s Disease, with the degeneration of DA neurons providing inputs to the striatum, the loss of the stimulatory effect on D1receptor expressing direct pathway neurons and the inhibitory effect on D2receptor expressing indirect pathway neurons results in the diminished ability to move symptomatic of the neurologic dysfunction of the disease. Treatment with the DA precursor, L-DOPA, restores the ability to move but over time produces uncontrolled involuntary dyskinetic movements, often of the face and arms. Work from our lab suggests that L-DOPA induced dyskinesia is caused by a change in the response of the D1receptor to L-DOPA treatment (Gerfen et al., 2002). Research in the laboratory of Alexandra Nelson at UCSF has identified a subset of D1receptor expressing neurons responsible for L-DOPA induced dyskinesia. A collaborative study completed this past year demonstrated that these neurons display excessive activity due to altered response to L-DOPA mediated effects on inputs from the cortex (Ryan et al., 2024). In a collaborative study with Huabin Cai’s laboratory in NIA, the “patch” and “matrix” striatal projection neurons were shown to have distinct and somewhat opposing effects on motor behavior. Whereas the striatal neurons expressing D1- and D2-dopamine receptors are intermingled throughout the striatum, a subset are organized in macroscopic compartments, termed the “patch and matrix”, which we originally demonstrated provide parallel circuits from the cortex through the striatum to distinct targets in the output nuclei of the basal ganglia (Gerfen, 1984). Using transgenic mice expressing Cre-recombinase selectively in striatal “patch” or “matrix” neurons, optogenetic manipulation demonstrated that “matrix” neurons promote locomotion by inhibiting GABAergic neurons in the substantia nigra pars reticulata, whereas “patch” striatonigral neurons terminate ongoing movement by inhibiting dopamine neurons in the substantia nigra pars compacta.