Biology subjects

Silberberg, H.

Publications and source records attributed to Silberberg, H..

4 recordsLinked to original sources

bioRxiv2024

The transcriptional response of cortical neurons to concussion reveals divergent fates after injury

Traumatic brain injury (TBI) is a risk factor for neurodegeneration, however little is known about how different neuron types respond to this kind of injury. In this study, we follow neuronal populations over several months after a single mild TBI (mTBI) to assess long ranging consequences of injury at the level of single, transcriptionally defined neuronal classes. We find that the stress responsive Activating Transcription Factor 3 (ATF3) defines a population of cortical neurons after mTBI. We show that neurons that activate ATF3 upregulate stress-related genes while repressing many genes, including commonly used markers for these cell types. Using an inducible reporter linked to ATF3, we genetically mark damaged cells to track them over time. Notably, we find that a population in layer V undergoes cell death acutely after injury, while another in layer II/III survives long term and retains the ability to fire action potentials. To investigate the mechanism controlling layer V neuron death, we genetically silenced candidate stress response pathways. We found that the axon injury responsive kinase MAP3K12, also known as dual leucine zipper kinase (DLK), is required for the layer V neuron death. This work provides a rationale for targeting the DLK signaling pathway as a therapeutic intervention for traumatic brain injury. Beyond this, our novel approach to track neurons after a mild, subclinical injury can inform our understanding of neuronal susceptibility to repeated impacts.

neuroscience↗

bioRxiv2022

Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla (RVM) contains neurons that robustly inhibit nociception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the RVM in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the RVM has never been achieved. We now expose a cellular circuit that inhibits nociception and itch in mice. Through a combination of molecular, tracing, and behavioral approaches, we found that RVM neurons containing the kappa-opioid receptor (KOR) inhibit itch and nociception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that RVMKOR neurons inhibit nociception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal gray (PAG) that modulates nociception within the RVM. These discoveries highlight a distinct population of RVM neurons capable of broadly and robustly inhibiting itch and nociception.

neuroscience↗

bioRxiv2020

Single nucleus RNA-sequencing defines unexpected diversity of cholinergic neuron types in the adult mouse spinal cord

In vertebrates, motor control relies on cholinergic neurons in the spinal cord that have been extensively studied over the past hundred years, yet the full heterogeneity of these neurons and their different functional roles in the adult remain to be defined. Here, we developed a targeted single nuclear RNA sequencing approach and used it to identify an array of cholinergic interneurons, visceral and skeletal motor neurons. Our data expose markers for distinguishing these classes of cholinergic neurons and their extremely rich diversity. Specifically, visceral motor neurons, which provide autonomic control, could be divided into more than a dozen transcriptomic classes with anatomically restricted localization along the spinal cord. The complexity of the skeletal motor neurons was also reflected in our analysis with alpha, beta, and gamma subtypes clearly distinguished. In combination, our data provide a comprehensive transcriptomic description of this important population of neurons that control many aspects of physiology and movement and encompass the cellular substrates for debilitating degenerative disorders.

neuroscience↗

bioRxiv2020

Ventral arkypallidal neurons modulate accumbal firing to promote reward consumption.

A pause in firing of nucleus accumbens shell (NAcSh) neurons is critical for reward consumption; however, the substrate driving this pause is unknown. While ventral pallidal (VP) activity encodes reward value, the specific roles of VP subpopulations in computation and expression of this value are poorly understood. Here, we establish that inhibitory input from the VP is crucial for reward-related inhibition of NAc firing. A sparse, non-canonical subpopulation of VP neurons, the so-called "ventral arkypallidal (vArky)" neurons makes inhibitory synaptic contacts throughout the NAcSh, and drives inhibition of NAcSh neurons in vivo. Moreover, endogenous calcium activity of vArky neurons predicted subsequent reward consumption behavior, while optogenetically activating this pathway increased reward consumption by amplifying hedonic value of reward. Classically, the VP is considered downstream of the NAc; however, our results challenge this view and establish that vArky neurons in the VP promote reward consumption via potent modulation of NAcSh firing.

neuroscience↗