Biology subjects

Sorensen, A. T.

Publications and source records attributed to Sorensen, A. T..

6 recordsLinked to original sources

bioRxiv2026

Vertical climbing in mice: a translationally relevant measure of pain-related impact on natural behaviour

Despite urgent need for better analgesics, drug development has been complicated by incomplete bench-to-bedside translation. A likely contributing factor is the poor connection between the experimenter-evoked pain-related measures often used in preclinical models, and the clinical symptoms, like broader functional impairment, reported by patients. Here, we asked whether vertical climbing, a species-specific elective behaviour in mice, could serve as a measure of pain-related impairment. We tested male and female mice in a wide range of pain-related models including models of post-operative pain, inflammatory injury, osteoarthritis, rheumatoid arthritis, cancer-induced bone pain, fibrous dysplasia, neuropathic pain, migraine-related pain and facial neuropathy. Vertical climbing was reduced in all models, across five different laboratories, demonstrating the robustness and consistency of this type of behaviour as a novel pain-related outcome measure. Reduced climbing correlated significantly with established pain-related measures, but its time course diverged from that of evoked mechanical allodynia, while aligned more closely with other non-evoked behaviours, like burrowing, home cage activity, wheel running or weight bearing. Pharmacological validation was bidirectional: gabapentin restored climbing in mice with neuropathic injury, and naltrexone reinstated the climbing deficit in mice that had recovered from intraplantar CFA, consistent with persistent pain held in remission by endogenous opioid signalling. Overall, our results indicate that voluntary vertical climbing is a stable, elective behaviour that provides a robust and translationally relevant measure of pain-related functional impairment in mice.

neuroscience↗

bioRxiv2024

Glutamate receptor-dependent cytosolic acidification in hippocampal neurons involves passive flux of protons from the extracellular space

Glutamate receptor-dependent cytosolic acidification can be induced in hippocampal neurons by pharmacological or seizure-like stimulation. This acidification is thought to arise from Ca2+ and metabolism-related processes, however, the exact underlying mechanism as well as its functional role remains uncertain. To reassess the mechanism of cytosolic acidification in excitatory hippocampal neurons and address the physiological relevance of the phenomenon, we combined pH/Ca2+ biosensors to study activity-induced pH dynamics in hippocampal neurons. First, we addressed cytosolic acidification in relation to LTP at hippocampal CA3-CA1 synapses. Using hippocampal slices from adult rats of both sexes, we show that LTP-inducing stimulation at the Schaffer collaterals evokes transient cytosolic acidification in hippocampal CA1 neurons. This highlights neuronal pH shifts as a trait of general hippocampal neurotransmission rather than a marker of excitotoxicity, possibly serving as a secondary messenger. Moreover, using dissociated hippocampal neurons from rat embryos, we show that glutamate receptor agonists typically induce larger cytosolic acid shifts compared to simple depolarization or spontaneous activity, suggesting that glutamate receptor-mediated acidification involves several separate mechanisms; pyruvate-dependent dampening of neuronal acidification may reflect a direct inhibition of NMDA receptors rather than reduced glycolytic activity, questioning the previously reported involvement of metabolism in cytosolic acidification; and whereas acid shifts induced by simple depolarization show exclusive dependence on cytosolic Ca2+, AMPA-induced acidification depends both on cytosolic Ca2+ and on an inward electrochemical driving force for protons. These results suggest that glutamate receptor-induced cytosolic acidification relies both on cytosolic Ca2+ and on a passive proton influx, possibly mediated by the receptor itself. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/624027v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1393cfcorg.highwire.dtl.DTLVardef@d2dc9corg.highwire.dtl.DTLVardef@191b24corg.highwire.dtl.DTLVardef@50b2f3_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance statementAlthough several studies report that hippocampal pyramidal neurons show significant cytosolic acidification in response to activation by drugs, epilepsy and stroke, the molecular mechanism and functional impact of the phenomenon remains uncertain. Using live imaging of both Ca and H dynamics, we demonstrate that the induction of LTP at hippocampal synapses is associated with cytosolic acidification in the postsynaptic neurons, suggesting that the cytosolic acid shifts may be a general trait of neurotransmission and related plasticity. We further revisit the mechanistic relation between the two ion systems. Our results suggest that glutamate receptor-induced cytosolic acidification involves two distinct mechanisms, one related to cytosolic Ca and another involving a passive H influx, possibly mediated by the receptor itself.

neuroscience↗

bioRxiv2023

Role of Dopamine Neurons in Familiarity

Dopamine neurons signal the salience of environmental stimuli, influencing learning and motivation. However, research has not yet identified whether dopamine neurons also modulate the salience of memory content. Dopamine neuron activity in the ventral tegmental area (VTA) increases in response to novel objects and diminishes as objects become familiar through repeated presentations. We proposed that the declined rate of dopamine neuron activity during familiarization affects the salience of a familiar objects memory. This, in turn, influences the degree to which an animal distinguishes between familiar and novel objects in a subsequent novel object recognition (NOR) test. As such, a single familiarization session may not sufficiently reduce dopamine activity, allowing the memory of a familiar object to maintain its salience and potentially attenuating NOR. In contrast, multiple familiarization sessions could lead to more pronounced dopamine activity suppression, strengthening NOR. Our data in mice reveals that, compared to a single session, multiple sessions result in decreased VTA dopamine neuron activation, as indicated by c-Fos measurements, and enhanced novelty discrimination. Critically, when VTA dopamine neurons are chemogenetically inhibited during a single familiarization session, NOR improves, mirroring the effects of multiple familiarization sessions. In summary, our findings highlight the pivotal function of dopamine neurons in familiarity and suggest a role in modulating the salience of memory content.

animal behavior and cognition↗

bioRxiv2022

Behavioral encoding across timescales by region-specificdopamine dynamics

The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled to behavioral outcomes. Here, we employ the dopamine sensor dLight1.3b together with multi-region fiber photometry and machine learning-based analysis to decode dopamine dynamics across striatum during self-paced exploratory behavior in mice. Our data show a striking coordination of rapidly fluctuating signal in the DS, carrying information across dopamine levels, with a slower signal in the VS, consisting mainly of slow-paced transients. Importantly, these release dynamics correlated with discrete behavioral motifs, such as turns, running and grooming on a subsecond-to-minutes time scale. Disruption of dopamine dynamics with cocaine caused randomization of action selection sequencing and disturbance of DS-VS coordination. The data suggest that distinct dopamine dynamics of DS and VS jointly encode behavioral sequences during unconstrained activity with DS modulating the stringing together of actions and VS the signal to initiate and sustain the selected action. Significance StatementNew genetically encoded dopamine sensors offer unprecedented temporal resolution for measurement of dopamine release dynamics across different brain regions over extended periods. In this study, we use the dopamine sensor dLight1.3b to decipher the role of dopamine release dynamics in the dorsal (DS) and ventral striatum (VS) of mice during simple, self-paced exploratory behavior. By AI-based splitting of behavioral kinematics into individual motifs, we link differential but highly cooperative dopamine release dynamics of DS and VS with movements on a subsecond-to-minutes time scales. In addition to coupling region-specific dopamine dynamics to behavioral sequences, our study demonstrates the strength of a machine learning-based data analysis pipeline that can be readily applied to other neurotransmitters for which genetically encoded biosensors are available.

neuroscience↗

bioRxiv2021

Nanoscopic dopamine transporter distribution and conformation are inversely regulated by excitatory drive and D2-autoreceptor activity

The nanoscopic organization and regulation of individual molecular components in presynaptic varicosities of neurons releasing modulatory volume neurotransmitters like dopamine (DA) remain largely elusive. Here we show by application of several super-resolution microscopy techniques to cultured neurons and mouse striatal slices, that the dopamine transporter (DAT), a key protein in varicosities of dopaminergic neurons, exists in the membrane in dynamic equilibrium between an inward-facing nanodomain-localized and outward-facing unclustered configuration. The balance between these configurations is inversely regulated by excitatory drive and by DA D2-autoreceptor activation in manner dependent on Ca2+-influx via N-type voltage-gated Ca2+-channels. The DAT nanodomains contain tens of transporters molecules and overlap with nanodomains of PIP2 (phosphatidylinositol-4,5-bisphosphate) but show little overlap with D2-autoreceptor, syntaxin-1 and clathrin nanodomains. Summarized, the data reveal a mechanism for rapid alterations in nanoscopic DAT distribution and show a striking link of this to the conformational state of the transporter.

neuroscience↗

bioRxiv2020

A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease

Dopaminergic dysfunction is central to movement disorders and mental diseases. The dopamine transporter (DAT) is essential for the regulation of extracellular dopamine but the genetic and mechanistic link between DAT function and dopamine-related pathologies remains elusive. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here we identify a novel coding DAT variant, DAT-K619N, in a patient with early-onset parkinsonism and comorbid neuropsychiatric disease and in 22 individuals from exome-sequenced samples of neuropsychiatric patients. The variant localizes to the critical C-terminal PDZ-binding motif of DAT and causes reduced uptake capacity, decreased surface expression, and accelerated turnover of DAT in vitro. In vivo, we demonstrate that expression of DAT-K619N in mice and dropsophila imposes impairments in dopamine transmission with accompanying changes in dopamine-directed behaviors. Importantly, both cellular studies and viral overexpression of DAT-K619N in mice show that DAT-K619N has a dominant-negative effect which collectively implies that a single dominant-negative genetic DAT variant can confer risk for neuropsychiatric disease and neurodegenerative early-onset parkinsonism.

neuroscience↗