Biology subjects

Tejeda, H. A.

Publications and source records attributed to Tejeda, H. A..

6 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↗

bioRxiv2024

Prefrontal cortical dynorphin peptidergic transmission constrains threat-driven behavioral and network states

Prefrontal cortical (PFC) circuits provide top-down control of threat reactivity. This includes ventromedial PFC (vmPFC) circuitry, which plays a role in suppressing fear-related behavioral states. Dynorphin (Dyn) has been implicated in mediating negative affect and mal-adaptive behaviors induced by severe threats and is expressed in limbic circuits, including the vmPFC. However, there is a critical knowledge gap in our understanding of how vmPFC Dyn-expressing neurons and Dyn transmission detect threats and regulate expression of defensive behaviors. Here, we demonstrate that Dyn cells are broadly activated by threats and release Dyn locally in the vmPFC to limit passive defensive behaviors. We further demonstrate that vmPFC Dyn-mediated signaling promotes a switch of vmPFC networks to a fear-related state. In conclusion, we reveal a previously unknown role of vmPFC Dyn neurons and Dyn neuropeptidergic transmission in suppressing defensive behaviors in response to threats via state-driven changes in vmPFC networks. Highlights[bullet] vmPFCDyn neurons are activated by threats and threat-predictive cues [bullet]Characterization of a genetically-encoded kappa-opioid receptor sensor [bullet]vmPFCDyn neurons rapidly release Dyn in response to threats and their predictors [bullet]vmPFCDyn signaling opposes threat-induced passive defensive behaviors [bullet]Dyn signaling promotes threat-evoked state transitions in vmPFC networks

neuroscience↗

bioRxiv2023

Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors

Dopamine release in striatal circuits, including the nucleus accumbens (NAc), tracks separable features of reward such as motivation and reinforcement. However, the cellular and circuit mechanisms by which dopamine receptors transform dopamine release into distinct constructs of reward remain unclear. Here, we show that dopamine D3 receptor (D3R) signaling in the NAc drives motivated behavior by regulating local NAc microcircuits. Furthermore, D3Rs co-express with dopamine D1 receptors (D1Rs), which regulate reinforcement, but not motivation. Paralleling dissociable roles in reward function, we report non-overlapping physiological actions of D3R and D1R signaling in NAc neurons. Our results establish a novel cellular framework wherein dopamine signaling within the same NAc cell type is physiologically compartmentalized via actions on distinct dopamine receptors. This structural and functional organization provides neurons in a limbic circuit with the unique ability to orchestrate dissociable aspects of reward-related behaviors that are relevant to the etiology of neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

Three-dimensional characterization of medium spiny neuron heterogeneity in the adult mouse striatum

Striatal projection neurons (SPNs) are traditionally segregated into two subpopulations expressing dopamine (DA) D1-like or D2-like receptors. However, this dichotomy is challenged by recent evidence. Functional and expression studies raise important questions: do SPNs co-express different DA receptors, and do these differences reflect unique striatal spatial distributions and expression profiles? Using RNAscope in mouse striatum, we report heterogenous SPN subpopulations distributed across dorsal-ventral and rostral-caudal axes. SPN subpopulations co-express multiple DA receptors, including D1 and D2 (D1/2R) and D1 and D3. Our integrative approach using single-nuclei multi-omics analyses provides a simple consensus to describe SPNs across diverse datasets, connecting it to complementary spatial mapping. Combining RNAscope and multi-omics shows D1/2R SPNs further separate into distinct subtypes according to spatial organization and conserved marker genes. Each SPN cell type contributes uniquely to genetic risk for neuropsychiatric diseases. Our results bridge anatomy and transcriptomics to offer new understandings of striatal neuron heterogeneity.

neuroscience↗

bioRxiv2022

Hippocampal cAMP-dependent synaptic potentiation, ERK-dependent immediate-early gene activation, and context-dependent fear conditioning in mice are linked through dependence on the guanine nucleotide exchange factor RapGEF2

The MAP kinase ERK is important for neuronal plasticity underlying associative learning, yet specific molecular pathways for ERK activation in hippocampus are still largely undetermined. RapGEF2 has emerged as a neuron-specific cAMP sensor that mediates ERK activation. We investigated whether RapGEF2 might also be required for cAMP-dependent ERK activation leading to synaptic potentiation, and how this involvement might be penetrant to hippocampus-dependent learned behavior. We demonstrate that conditional knockout of Rapgef2 in forebrain neurons, specifically in dentate gyrus and CA1 of the hippocampus, leads to an attenuation of context-dependent fear conditioning, but not of cue-dependent fear conditioning, in mice. RapGEF2 knockout is associated with a reduction in cAMP-dependent synaptic potentiation at two central hippocampal synapses-the entorhinal cortex-granule cell synapse and the CA3-CA1 synapse. Furthermore, cAMP-induced postsynaptic potentiation requires both RapGEF2 and activation of ERK. Induction of Egr-1/Zif268 (and pERK), but not of c-Fos, immediately following fear conditioning, was abolished in CA1 and detate gyrus, in the absence of RapGEF2 expression in these hippocampal regions, thus revealing a link between learning (conditioning) and molecular pathways activated during conditioned fear memory formation. Hence, we suggest that contextual fear conditioning is mediated via RapGEF2-dependent ERK activation and downstream induction of Egr-1, via an underlying mechanism of cAMP-dependent long-term potentiation at hippocampal synapses. Cyclic AMP-dependent GEFs have been genetically associated as risk factors for schizophrenia, a disorder associated with cognitive deficits. This study provides a functional link between one of these cAMP-dependent GEFs, RapGEF2, and cognitive processes involved in associative learning.

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bioRxiv2020

Cocaine-dependent acquisition of locomotor sensitization and conditioned place preference requires D1 dopaminergic signaling through a cyclic AMP, NCS-Rapgef2, ERK and Egr-1/Zif268 pathway

Elucidation of the underlying mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor expressingneurons leadingto acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERK[->]Egr-1/zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons (MSNs) of nucleus accumbens slices; and in mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the nucleus accumbens (NAc) in adult mice, using AAV-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation in D1-MSNs and cocaine-induced behaviors including locomotor sensitization and conditioned place preference (CPP). Abrogation of NCS-Rapgef2 gene expression in medium prefrontal cortex and basolateral amygdala, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium/calmodulin-dependent kinase II promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1-receptor expressing neurons in the NAc, butnotin corticolimbic areas, contributes to cocaine-induced locomotor sensitization and CPP. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2/phospho-ERK activation, independently of PKA/CREB signaling. SIGNIFICANCE STATEMENTERK phosphorylation in dopamine D1 receptor expressing neurons exerts a pivotal role in psychostimulant-induced neuronal gene regulation and behavioraladaptation, including locomotor sensitization and drug preference in rodents. In this study, we examined the role of dopamine signaling through the D1 receptor via a novel pathway initiated through the cAMP-activated guanine nucleotide exchange factor NCS-Rapgef2 in mice. NCS-Rapgef2 in the nucleus accumbens is required for activation of ERK and Egr-1/Zif268 in D1 dopaminoceptive neurons after acute cocaine administration, and subsequentenhanced locomotor response anddrugseeking behavior after repeated cocaine administration. This novel component in dopamine signaling provides a potential new target for intervention in psychostimulant-shaped behaviors, and new understanding of how D1-MSNs encode the experience of psychomotor stimulant exposure.

neuroscience↗