Publications by authors named "Linette Liqi Tan"

9 Publications

  • Page 1 of 1

Neurogenesis in the adult brain functionally contributes to the maintenance of chronic neuropathic pain.

Sci Rep 2021 09 17;11(1):18549. Epub 2021 Sep 17.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.

Maladaptive adult neurogenesis in the mammalian brain has been associated with diverse behaviors including disrupted learning, negative mood disorders and psychiatric conditions. However, its functional role in the generation and maintenance of chronic pathological pain has not yet been elucidated. Using an inducible genetic deletion in vivo mouse model, different behavioural paradigms and home cage monitoring systems, we show that an absence of adult neurogenesis does not impact the development of neuropathic injury-induced peripheral nociceptive hypersensitivity, but rather promotes the recovery of pathological pain as well as improves parameters associated with the state of well-being of the injured mice. These results provide a mechanistic insight into the mechanisms of chronic pain and implicate neurogenic processes as a potential therapeutic target for reducing pain and improving the quality of life for patients.
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http://dx.doi.org/10.1038/s41598-021-97093-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448753PMC
September 2021

Neurobiology of brain oscillations in acute and chronic pain.

Trends Neurosci 2021 08 24;44(8):629-642. Epub 2021 Jun 24.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, D-69120 Heidelberg, Germany. Electronic address:

Pain is a complex perceptual phenomenon. Coordinated activity among local and distant brain networks is a central element of the neural underpinnings of pain. Brain oscillatory rhythms across diverse frequency ranges provide a functional substrate for coordinating activity across local neuronal ensembles and anatomically distant brain areas in pain networks. This review addresses parallels between insights from human and rodent analyses of oscillatory rhythms in acute and chronic pain and discusses recent rodent-based studies that have shed light on mechanistic underpinnings of brain oscillatory dynamics in pain-related behaviors. We highlight the potential for therapeutic modulation of oscillatory rhythms, and identify outstanding questions and challenges to be addressed in future research.
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http://dx.doi.org/10.1016/j.tins.2021.05.003DOI Listing
August 2021

Neocortical circuits in pain and pain relief.

Nat Rev Neurosci 2021 08 14;22(8):458-471. Epub 2021 Jun 14.

Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.

The sensory, associative and limbic neocortical structures play a critical role in shaping incoming noxious inputs to generate variable pain perceptions. Technological advances in tracing circuitry and interrogation of pathways and complex behaviours are now yielding critical knowledge of neocortical circuits, cellular contributions and causal relationships between pain perception and its abnormalities in chronic pain. Emerging insights into neocortical pain processing suggest the existence of neocortical causality and specificity for pain at the level of subdomains, circuits and cellular entities and the activity patterns they encode. These mechanisms provide opportunities for therapeutic intervention for improved pain management.
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http://dx.doi.org/10.1038/s41583-021-00468-2DOI Listing
August 2021

Repetitive non-invasive prefrontal stimulation reverses neuropathic pain via neural remodelling in mice.

Prog Neurobiol 2021 06 20;201:102009. Epub 2021 Feb 20.

Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Electronic address:

Chronic neuropathic pain presents a major challenge to pharmacological therapy and neurostimulation-based alternatives are gaining interest. Although invasive and non-invasive motor cortex stimulation has been the focus of several studies, very little is known about the potential of targeting the prefrontal cortex. This study was designed to elucidate the analgesic potential of prefrontal stimulation in a translational context and to uncover the neural underpinnings thereof. Here, we report that non-invasive, repetitive direct anodal current transcranial stimulation (tDCS) of the prefrontal cortex exerted analgesia in mice with neuropathic pain for longer than a week. When applied at chronic stages of neuropathic pain, prefrontal tDCS reversed established allodynia and suppressed aversion and anxiety-related behaviours. Activity mapping as well as in vivo electrophysiological analyses revealed that although the cortex responds to acute tDCS with major excitation, repetitive prefrontal tDCS brings about large-scale silencing of cortical activity. Different classes of different classes of GABAergic interneurons and classes of excitatory neurons differs dramatically between single, acute vs and repetitive tDCS. Repetitive prefrontal tDCS alters basal activity as well as responsivity of a discrete set of distant cortical and sub-cortical areas to tactile stimuli, namely the rostral anterior cingulate cortex, the insular cortex, the ventrolateral periaqueductal grey and the spinal dorsal horn. This study thus makes a strong case for harnessing prefrontal cortical modulation for non-invasive transcranial stimulation paradigms to achieve long-lasting pain relief in established neuropathic pain states and provides valuable insights gained on neural mechanistic underpinnings of prefrontal tDCS in neuropathic pain.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102009DOI Listing
June 2021

Functional disruption of cortical cingulate activity attenuates visceral hypersensitivity and anxiety induced by acute experimental colitis.

Sci Rep 2021 01 22;11(1):2103. Epub 2021 Jan 22.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.

Visceral pain is a highly complex experience and is the most common pathological feature in patients suffering from inflammatory gastrointestinal disorders. Whilst it is increasingly recognized that aberrant neural processing within the gut-brain axis plays a key role in development of neurological symptoms, the underlying mechanisms remain largely unknown. Here, we investigated the cortical activation patterns and effects of non-invasive chemogenetic suppression of cortical activity on visceral hypersensitivity and anxiety-related phenotypes in a well-characterized mouse model of acute colitis induced by dextran sulfate sodium (DSS). We found that within the widespread cortical network, the mid-cingulate cortex (MCC) was consistently highly activated in response to innocuous and noxious mechanical stimulation of the colon. Furthermore, during acute experimental colitis, impairing the activity of the MCC successfully alleviated visceral hypersensitivity, anxiety-like behaviors and visceromotor responses to colorectal distensions (CRDs) via downregulating the excitability of the posterior insula (PI), somatosensory and the rostral anterior cingulate cortices (rACC), but not the prefrontal or anterior insula cortices. These results provide a mechanistic insight into the central cortical circuits underlying painful visceral manifestations and implicate MCC plasticity as a putative target in cingulate-mediated therapies for bowel disorders.
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http://dx.doi.org/10.1038/s41598-021-81256-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822936PMC
January 2021

Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain.

Mol Psychiatry 2021 Sep 1;26(9):4616-4632. Epub 2020 Jul 1.

Department of Clinical Neurobiology, University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany.

In mammals, most adult neural stem cells (NSCs) are located in the ventricular-subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior-ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.
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http://dx.doi.org/10.1038/s41380-020-0823-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589654PMC
September 2021

Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception.

Nat Commun 2019 02 28;10(1):983. Epub 2019 Feb 28.

Pharmacology Institute, Medical Faculty Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.

In humans, gamma-band oscillations in the primary somatosensory cortex (S1) correlate with subjective pain perception. However, functional contributions to pain and the nature of underlying circuits are unclear. Here we report that gamma oscillations, but not other rhythms, are specifically strengthened independently of any motor component in the S1 cortex of mice during nociception. Moreover, mice with inflammatory pain show elevated resting gamma and alpha activity and increased gamma power in response to sub-threshold stimuli, in association with behavioral nociceptive hypersensitivity. Inducing gamma oscillations via optogenetic activation of parvalbumin-expressing inhibitory interneurons in the S1 cortex enhances nociceptive sensitivity and induces aversive avoidance behavior. Activity mapping identified a network of prefrontal cortical and subcortical centers whilst morphological tracing and pharmacological studies demonstrate the requirement of descending serotonergic facilitatory pathways in these pain-related behaviors. This study thus describes a mechanistic framework for modulation of pain by specific activity patterns in the S1 cortex.
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http://dx.doi.org/10.1038/s41467-019-08873-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395755PMC
February 2019

A pathway from midcingulate cortex to posterior insula gates nociceptive hypersensitivity.

Nat Neurosci 2017 Nov 18;20(11):1591-1601. Epub 2017 Sep 18.

Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.

The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC-posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain.
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http://dx.doi.org/10.1038/nn.4645DOI Listing
November 2017
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