Differential contributions of distinct pallidal pathways to behavioral deficits in a mouse model of Parkinson's disease

The external segment of the globus pallidus (GPe), a subcortical nucleus centrally located in the indirect pathway of the basal ganglia, plays a pivotal role in processing and broadcasting information received from the striatum and the subthalamic nucleus through its widespread projections across major basal ganglia nuclei. One of the largest neuronal populations of the GPe expresses the Ca2+-binding protein parvalbumin (PV) and projects to multiple nuclei of the basal ganglia and the thalamus and has been shown to be involved in movement disability in Parkinson’s disease (PD). However, most studies to date considered GPe PV neurons as a homogeneous population. We found that the GPe PV neurons can be further subdivided into two non-overlapping populations based on their projections to either the substantia nigra pars reticulata (SNr) or the parafascicular thalamus (PF) and their intrinsic electrophysiological properties. We further investigated the circuit-specific roles of these subpopulations in locomotion and reversal learning as well as their contributions to the impairments of motor and cognitive flexibility in a PD mouse model. Our findings establish the behavioral significance of two distinct GPe PV neuronal populations embedded in discrete neural pathways and their differential contributions to specific subdomains of Parkinsonian-like behaviors

Differential contributions of distinct pallidal pathways to behavioral deficits in a mouse model of Parkinson's disease

The external segment of the globus pallidus (GPe), a subcortical nucleus centrally located in the indirect pathway of the basal ganglia, plays a pivotal role in processing and broadcasting information received from the striatum and the subthalamic nucleus through its widespread projections across major basal ganglia nuclei. One of the largest neuronal populations of the GPe expresses the Ca2+-binding protein parvalbumin (PV) and projects to multiple nuclei of the basal ganglia and the thalamus and has been shown to be involved in movement disability in Parkinson’s disease (PD). However, most studies to date considered GPe PV neurons as a homogeneous population. We found that the GPe PV neurons can be further subdivided into two non-overlapping populations based on their projections to either the substantia nigra pars reticulata (SNr) or the parafascicular thalamus (PF) and their intrinsic electrophysiological properties. We further investigated the circuit-specific roles of these subpopulations in locomotion and reversal learning as well as their contributions to the impairments of motor and cognitive flexibility in a PD mouse model. Our findings establish the behavioral significance of two distinct GPe PV neuronal populations embedded in discrete neural pathways and their differential contributions to specific subdomains of Parkinsonian-like behaviors

Recurrent circuits within medial entorhinal cortex superficial layers support grid cell firing

Medial entorhinal cortex (mEC) neurons encode various navigation parameters such as speed, head direction, as well as grid cells. Here, the authors demonstrate that brief disruption of the local activity in mEC specifically affects grid cell tuning

Distinct Ventral Pallidal Neural Populations Mediate Separate Symptoms of Depression

Major depressive disorder (MDD) patients display a common but often variable set of symptoms making successful, sustained treatment difficult to achieve. Separate depressive symptoms may be encoded by differential changes in distinct circuits in the brain, yet how discrete circuits underlie behavioral subsets of depression and how they adapt in response to stress has not been addressed. We identify two discrete circuits of parvalbumin-positive (PV) neurons in the ventral pallidum (VP) projecting to either the lateral habenula or ventral tegmental area contributing to depression. We find that these populations undergo different electrophysiological adaptations in response to social defeat stress, which are normalized by antidepressant treatment. Furthermore, manipulation of each population mediates either social withdrawal or behavioral despair, but not both. We propose that distinct components of the VP PV circuit can subserve related, yet separate depressive-like phenotypes in mice, which could ultimately provide a platform for symptom-specific treatments of depression

Voluntary urination control by brainstem neurons that relax the urethral sphincter.

Voluntary urination ensures that waste is eliminated when safe and socially appropriate, even without a pressing urge. Uncontrolled urination, or incontinence, is a common problem with few treatment options. Normal urine release requires a small region in the brainstem known as Barrington's nucleus (Bar), but specific neurons that relax the urethral sphincter and enable urine flow are unknown. Here we identify a small subset of Bar neurons that control the urethral sphincter in mice. These excitatory neurons express estrogen receptor 1 (BarESR1), project to sphincter-relaxing interneurons in the spinal cord and are active during natural urination. Optogenetic stimulation of BarESR1 neurons rapidly initiates sphincter bursting and efficient voiding in anesthetized and behaving animals. Conversely, optogenetic and chemogenetic inhibition reveals their necessity in motivated urination behavior. The identification of these cells provides an expanded model for the control of urination and its dysfunction

Voluntary urination control by brainstem neurons that relax the urethral sphincter.

Voluntary urination ensures that waste is eliminated when safe and socially appropriate, even without a pressing urge. Uncontrolled urination, or incontinence, is a common problem with few treatment options. Normal urine release requires a small region in the brainstem known as Barrington's nucleus (Bar), but specific neurons that relax the urethral sphincter and enable urine flow are unknown. Here we identify a small subset of Bar neurons that control the urethral sphincter in mice. These excitatory neurons express estrogen receptor 1 (BarESR1), project to sphincter-relaxing interneurons in the spinal cord and are active during natural urination. Optogenetic stimulation of BarESR1 neurons rapidly initiates sphincter bursting and efficient voiding in anesthetized and behaving animals. Conversely, optogenetic and chemogenetic inhibition reveals their necessity in motivated urination behavior. The identification of these cells provides an expanded model for the control of urination and its dysfunction

Activation of Pedunculopontine Glutamate Neurons Is Reinforcing.

Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders.Significance statementUncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and behavioral reinforcement

Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors

Chronic stress (CS) is a major risk factor for the development of depression. Here, we demonstrate that CS-induced hyperactivity in ventral tegmental area (VTA)-projecting lateral habenula (LHb) neurons is associated with increased passive coping (PC), but not anxiety or anhedonia. LHb→VTA neurons in mice with increased PC show increased burst and tonic firing as well as synaptic adaptations in excitatory inputs from the entopeduncular nucleus (EP). In vivo manipulations of EP→LHb or LHb→VTA neurons selectively alter PC and effort-related motivation. Conversely, dorsal raphe (DR)-projecting LHb neurons do not show CS-induced hyperactivity and are targeted indirectly by the EP. Using single-cell transcriptomics, we reveal a set of genes that can collectively serve as biomarkers to identify mice with increased PC and differentiate LHb→VTA from LHb→DR neurons. Together, we provide a set of biological markers at the level of genes, synapses, cells, and circuits that define a distinctive CS-induced behavioral phenotype

Protection of tissue physicochemical properties using polyfunctional crosslinkers

Understanding complex biological systems requires the system-wide characterization of both molecular and cellular features. Existing methods for spatial mapping of biomolecules in intact tissues suffer from information loss caused by degradation and tissue damage. We report a tissue transformation strategy named stabilization under harsh conditions via intramolecular epoxide linkages to prevent degradation (SHIELD), which uses a flexible polyepoxide to form controlled intra-and intermolecular cross-link with biomolecules. SHIELD preserves protein fluorescence and antigenicity, transcripts and tissue architecture under a wide range of harsh conditions. We applied SHIELD to interrogate system-level wiring, synaptic architecture, and molecular features of virally labeled neurons and their targets in mouse at single-cell resolution. We also demonstrated rapid three-dimensional phenotyping of core needle biopsies and human brain cells. SHIELD enables rapid, multiscale, integrated molecular phenotyping of both animal and clinical tissues.NIH (Grant 1-DP2-ES027992)NIMH (Grants R01MH107742, R01MH108594, U01MH114829

Corticostriatal Flow of Action Selection Bias

The posterior parietal cortex (PPC) performs many functions, including decision making and movement control. It remains unknown which input and output pathways of PPC support different functions. We addressed this issue in mice, focusing on PPC neurons projecting to the dorsal striatum (PPC-STR) and the posterior secondary motor cortex (PPC-pM2). Projection-specific, retrograde labeling showed that PPC-STR and PPC-pM2 represent largely distinct subpopulations, with PPC-STR receiving stronger inputs from association areas and PPC-pM2 receiving stronger sensorimotor inputs. Two-photon calcium imaging during decision making revealed that the PPC-STR population encodes history-dependent choice bias more strongly than PPC-pM2 or general PPC populations. Furthermore, optogenetic inactivation of PPC-STR neurons or their terminals in STR decreased history-dependent bias, while inactivation of PPC-pM2 neurons altered movement kinematics. Therefore, PPC biases action selection through its STR projection while controlling movements through PPC-pM2 neurons. PPC may support multiple functions through parallel subpopulations, each with distinct input-output connectivity