Biology subjects

Silberberg, G.

Publications and source records attributed to Silberberg, G..

8 recordsLinked to original sources

bioRxiv2024

Motor cortex directly excites the output nucleus of the basal ganglia, the substantia nigra pars reticulata.

Inhibitory neurons of the substantia nigra pars reticulata (SNr) serve as a primary output through which the basal ganglia regulate behaviour. Projections to the SNr from beyond the basal ganglia have also been identified anatomically. Using a virally-targeted optogenetic approach, combined with whole cell patch-clamp recordings of SNr neurons in acute brain slices, we show that projection neurons of the primary and secondary motor cortices (M1 and M2) make functional excitatory synapses with subpopulations of inhibitory SNr neurons. Furthermore, we demonstrate that photostimulation of these cortical axon terminals increases SNr neuron firing rate. To further investigate the spatial organisation of cortical input to SNr, we employed a transsynaptic viral-labelling approach to identify SNr neurons receiving monosynaptic input from M1 and M2. We found a topographical relationship between motor cortex and SNr, and identified downstream targets of cortical-recipient SNr subpopulations. These findings reveal functional pathways by which M1 and M2 can directly modulate basal ganglia output to different downstream targets.

neuroscience↗

bioRxiv2023

Serotonergic and dopaminergic neurons in the dorsal raphe are differentially altered in a mouse model for Parkinson's disease.

Parkinsons disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor co-morbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both noradrenaline and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.

neuroscience↗

bioRxiv2023

Presynaptic and Postsynaptic Determinants of the Functional Connectivity Between the Claustrum and Anterior Cingulate Cortex.

The claustrum (CLA) is a brain nucleus located between the insula and lateral striatum, implicated in a wide range of behaviors. Underpinning the different behavioral phenotypes is the connectivity between the claustrum and various cortical regions, including the anterior cingulate cortex (ACC). CLA projection neurons are glutamatergic neurons, however, the impact of CLA on its cortical targets has been shown in some studies to be inhibitory. Such inhibition is likely to arise from claustral activation of cortical interneurons, however, the intricate synaptic connectivity between different CLA and cortical cell types is not known. Here, we combine in vivo and ex vivo electrophysiology and optogenetics to reveal the functional organization of the CLA-ACC pathway according to the identity of its pre- and postsynaptic populations. Optogenetic stimulation of CLA neurons in awake mice resulted in multiphasic excitatory and inhibitory responses in ACC cells, which depended on the layer, cell type, and stimulated CLA population. Using ex vivo paired recordings in ACC, monosynaptic responses were recorded in pyramidal cells and different types of interneurons following photostimulation of CLA-ACC synaptic terminals. CLA axons formed monosynaptic connections in all ACC cortical layers, but the probability and strength of synaptic responses depended on the type of CLA projection, target layer in ACC, and the type of postsynaptic neuron. This intricate organization of the CLA-ACC pathway may explain the complex impact of CLA on ACC and other cortical regions, thus resolving some of the discrepancies in the field and shedding light on the functional role CLA plays in cortical function.

neuroscience↗

bioRxiv2022

Pharmaco-Pheno-Multiomic Integration Reveals Biomarker Profiles and Therapeutic Response Prediction Models in Leukemia and Ovarian Cancer

Despite considerable progress made in improving therapeutic strategies, the overall survival for patients diagnosed with various cancer types remains low. Further, patients often cycle through multiple therapeutic options before finding an effective regimen for the specific malignancy being treated. A focus on building enhanced computational models, which prioritize therapeutic regimens based on a tumors complete molecular profile, will improve the patient experience and augment initial outcomes. In this study, we present an integrative analysis of multiple omic datasets coupled with phenotypic and therapeutic response profiles of Cytarabine from a cohort of primary AML tumors, and Olaparib from a cohort of Patient-Derived Xenograft (PDX) models of ovarian cancer. These analyses, termed Pharmaco-Pheno-Multiomic (PPMO) Integration, established novel complex biomarker profiles that were used to accurately predict prospective therapeutic response profiles in cohorts of newly profiled AML and ovarian tumors. Results from the computational analyses also provide new insights into disease etiology and the mechanisms of therapeutic resistance. Collectively, this study provides proof-of-concept in the use of PPMO to establish highly accurate predictive models of therapeutic response, and the power of leveraging this method to unveil cancer disease mechanisms.

cancer biology↗

bioRxiv2022

Sensory responses in dorsolateral striatum are modulated by motor activity in a dopamine-dependent manner

The dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cortical regions and is involved in sensory and motor functions. In cortical regions, sensory responses are altered by motor activity, however, it is not known if such sensorimotor interactions also occur in the striatum and how they are modulated by dopamine (DA). To determine the impact of motor activity on striatal sensory processing, we performed in vivo whole-cell recordings in the DLS of awake mice during the presentation of tactile stimuli. Striatal medium spiny neurons (MSNs) were activated by both whisker stimulation and spontaneous whisking, however, responses to whisker deflection during ongoing whisking were attenuated. DA depletion reduced the representation of whisking in direct-pathway MSNs, but not in those of the indirect-pathway. Furthermore, DA depletion impaired the discrimination between ipsi- and contralateral sensory stimulation in both direct- and indirect- pathway MSNs. Our results show that sensory responses in basal ganglia circuits are modulated by motor activity and that both processes are dopamine- and cell type-dependent.

neuroscience↗

bioRxiv2021

Tonic engagement of nicotinic receptors bidirectionally controls striatal spiny projection neuron spike timing

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can disynaptically inhibit SPNs by activating 4{beta}2 nicotinic acetylcholine receptors (nAChRs) on various GINs. Measurements of this disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that respond only weakly to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices we show that upon synchronous optogenetic activation of corticostriatal projections blockade of 4{beta}2 nAChRs shortened SPN spike latencies and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond strongly to phasic CIN activation. In particular, the observed decrease in spike latency caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, a parallel hyperpolarization of PV-FSIs, and was occluded by pharmacologically preventing cortical activation of PV-FSIs. Taken together, we describe a role for tonic (as opposed to phasic) activation of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs maintains a GABAergic brake on cortically-driven striatal output by "priming" feedforward inhibition, a process that may shape SPN spike timing, striatal processing and synaptic plasticity. Impact StatementA novel mechanism describing how tonic activation of nicotinic acetylcholine receptors can modulate the timing of striatal output by priming feed forward inhibition.

neuroscience↗

bioRxiv2020

Differential Synaptic Input to External Globus Pallidus Neuronal Subpopulations In Vivo.

The rodent external Globus Pallidus (GPe) contains two main neuronal subpopulations, prototypic and arkypallidal cells, which differ in their cellular properties. Their functional synaptic connectivity is, however, largely unknown. Here, we studied the membrane properties and synaptic inputs to these subpopulations in the mouse GPe. We obtained in vivo whole-cell recordings from identified GPe neurons and used optogenetic stimulation to dissect their afferent inputs from the striatum and subthalamic nucleus (STN). All GPe neurons received barrages of excitatory and inhibitory input during slow wave activity. The modulation of their activity was cell-type specific and shaped by their respective membrane properties and afferent inputs. Both GPe subpopulations received synaptic input from STN and striatal projection neurons (MSNs). STN and indirect pathway MSNs strongly targeted prototypic cells while direct pathway MSNs selectively inhibited arkypallidal cells. We show that GPe subtypes are differently embedded in the basal ganglia network, supporting distinct functional roles.

neuroscience↗

bioRxiv2019

Direct Pathway Neurons in Mouse Dorsolateral Striatum In Vivo Receive Stronger Synaptic Input than Indirect Pathway Neurons

Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1 or D2 type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modelling of the striatal network has predicted that under healthy conditions dMSNs should receive more excitatory input than iMSNs. To test this prediction, we analyzed in vivo whole-cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized towards the spike threshold significantly faster than iMSNs did. Together, these finding corroborate the theoretical prediction that direct-pathway MSNs receive stronger input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question how a lack of dopamine may lead to behavior deficits associated with Parkinsons disease.\n\nSignificance statementThe direct and indirect pathways of the basal ganglia originate from the D1 and D2 type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs), respectively. To understand the role of the striatum in brain function and dysfunction it is important to characterize the differences in synaptic inputs to the two MSN types. Theoretical results predicted that dMSNs should receive stronger excitatory input than iMSNs. Here, we studied membrane potential fluctuation statistics of MSNs recorded in vivo in anaesthetized mice and found that dMSNs, indeed, received stronger synaptic input than iMSNs. We corroborated this finding by spike-triggered membrane potential analysis, showing that dMSNs spiking required more synaptic input than iMSNs spiking did, as had been predicted by computational models.

neuroscience↗