Disrupted population coding in the prefrontal cortex underlies pain aversion

Li, Anna; Liu, Yaling; Zhang, Qiaosheng; Friesner, Isabel D.; Jee, Hyun Jung; Chen, Zhe; Wang, Jing

doi:10.1016/j.celrep.2021.109978

Cited by 15 publications

(11 citation statements)

References 79 publications

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“…We then attached a single-photon miniscope to the GRIN lens to track Ca 2+ activity within CAMKII-expressing neurons, which are mostly excitatory neurons. 37 , 38 For each recording session, we measured Ca 2+ activity for 5 min with no external stimuli for a baseline measurement ( Figure 3(c) ). We then measured Ca 2+ activity after the delivery of a non-noxious von Frey (vF) mechanical stimulus versus the delivery of the PP stimulus.…”

Section: Resultsmentioning

confidence: 99%

AMPAkines have site-specific analgesic effects in the cortex

Zhu,

Mathew,

Jee

et al. 2024

Mol Pain

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Different brain areas have distinct roles in the processing and regulation of pain and thus may form specific pharmacological targets. Prior research has shown that AMPAkines, a class of drugs that increase glutamate signaling, can enhance descending inhibition from the prefrontal cortex (PFC) and nucleus accumbens. On the other hand, activation of neurons in the anterior cingulate cortex (ACC) is known to produce the aversive component of pain. The impact of AMPAkines on ACC, however, is not known. We found that direct delivery of CX516, a well-known AMPAkine, into the ACC had no effect on the aversive response to pain in rats. Furthermore, AMPAkines did not modulate the nociceptive response of ACC neurons. In contrast, AMPAkine delivery into the prelimbic region of the prefrontal cortex (PL) reduced pain aversion. These results indicate that the analgesic effects of AMPAkines in the cortex are likely mediated by the PFC but not the ACC.

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Section: Resultsmentioning

confidence: 99%

AMPAkines have site-specific analgesic effects in the cortex

Zhu,

Mathew,

Jee

et al. 2024

Mol Pain

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“…However, stimulus representation on the cellular level tends to continuously reconfigure in associative areas, despite stable behavioral performance ( 30 – 32 ). It is currently unclear how the temporal dynamics of nociceptive representation in higher cortical areas evolve over time at the cellular level ( 33 ). Resolving this question will help to understand if sensory representation and particularly nociception and its quality-specificity are achieved through hard-wired, stable and dedicated neurons or by flexible and dynamic neuronal ensembles.…”

Section: Resultsmentioning

confidence: 99%

Principles of nociceptive coding in the anterior cingulate cortex

Acuña

Kasanetz

Luna

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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The perception of pain is a multidimensional sensory and emotional/affective experience arising from distributed brain activity. However, the involved brain regions are not specific for pain. Thus, how the cortex distinguishes nociception from other aversive and salient sensory stimuli remains elusive. Additionally, the resulting consequences of chronic neuropathic pain on sensory processing have not been characterized. Using in vivo miniscope calcium imaging with cellular resolution in freely moving mice, we elucidated the principles of nociceptive and sensory coding in the anterior cingulate cortex, a region essential for pain processing. We found that population activity, not single-cell responses, allowed discriminating noxious from other sensory stimuli, ruling out the existence of nociception-specific neurons. Additionally, single-cell stimulus selectivity was highly dynamic over time, but stimulus representation at the population level remained stable. Peripheral nerve injury-induced chronic neuropathic pain led to dysfunctional encoding of sensory events by exacerbation of responses to innocuous stimuli and impairment of pattern separation and stimulus classification, which were restored by analgesic treatment. These findings provide a novel interpretation for altered cortical sensory processing in chronic neuropathic pain and give insights into the effects of systemic analgesic treatment in the cortex.

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“…This cortical gain may have been disrupted when acute pain turned into chronic pain. 51 , 57 Whether this cortical gain still exists in other timepoints needs to be explored in the future study.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, this hyperalgesia signal might activate those pain-responsive neurons to potentiate synaptic transmission in the IL as a cortical gain projecting to the CeLC to prevent OIH. 51 , 57 It probably acts as a compensatory mechanism to the attenuative effects on amygdala of the decreased PL excitability under similar circumstances. However, this cortical gain of IL may be too weak to compensate for the hyperactivity of the CeLC, 7 , 8 , 10 so that the hyperalgesic state persists.…”

Section: Discussionmentioning

confidence: 99%

Projections from infralimbic medial prefrontal cortex glutamatergic outputs to amygdala mediates opioid induced hyperalgesia in male rats

Cui,

Wang,

Liu

et al. 2024

Mol Pain

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Repeated use of opioid analgesics may cause a paradoxically exacerbated pain known as opioid-induced hyperalgesia (OIH), which hinders effective clinical intervention for severe pain. Currently, little is known about the neural circuits underlying OIH modulation. Previous studies suggest that laterocapsular division of the central nucleus of amygdala (CeLC) is critically involved in the regulation of OIH. Our purpose is to clarify the role of the projections from infralimbic medial prefrontal cortex (IL) to CeLC in OIH. We first produced an OIH model by repeated fentanyl subcutaneous injection in male rats. Immunofluorescence staining revealed that c-Fos-positive neurons were significantly increased in the right CeLC in OIH rats than the saline controls. Then, we used calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) labeling and the patch-clamp recordings with ex vivo optogenetics to detect the functional projections from glutamate pyramidal neurons in IL to the CeLC. The synaptic transmission from IL to CeLC, shown in the excitatory postsynaptic currents (eEPSCs), inhibitory postsynaptic currents (eIPSCs) and paired-pulse ratio (PPR), was observably enhanced after fentanyl administration. Moreover, optogenetic activation of this IL-CeLC pathway decreased c-Fos expression in CeLC and ameliorated mechanical and thermal pain in OIH. On the contrary, silencing this pathway by chemogenetics exacerbated OIH by activating the CeLC. Combined with the electrophysiology results, the enhanced synaptic transmission from IL to CeLC might be a cortical gain of IL to relieve OIH rather than a reason for OIH generation. Scaling up IL outputs to CeLC may be an effective neuromodulation strategy to treat OIH.

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Disrupted population coding in the prefrontal cortex underlies pain aversion

Cited by 15 publications

References 79 publications

AMPAkines have site-specific analgesic effects in the cortex

AMPAkines have site-specific analgesic effects in the cortex

Principles of nociceptive coding in the anterior cingulate cortex

Projections from infralimbic medial prefrontal cortex glutamatergic outputs to amygdala mediates opioid induced hyperalgesia in male rats

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