Release of endogenous dynorphin opioids in the prefrontal cortex disrupts cognition

Following repeated opioid use, some dependent individuals experience persistent cognitive deficits that contribute to relapse of drug-taking behaviors, and one component of this response may be mediated by the endogenous dynorphin/kappa opioid system in neocortex. In mice, we find that acute morphine withdrawal evokes dynorphin release in the medial prefrontal cortex (PFC) and disrupts cognitive function by activation of local kappa opioid receptors (KORs). Immunohistochemical analyses using a phospho-KOR antibody confirmed that both withdrawal-induced and optically evoked dynorphin release activated KOR in PFC. Using a genetically encoded sensor based on inert KOR (kLight1.2a), we revealed the in vivo dynamics of endogenous dynorphin release in the PFC. Local activation of KOR in PFC produced multi-phasic disruptions of memory processing in an operant delayed alternation behavioral task, which manifest as reductions in response number and accuracy during early and late phases of an operant session. Local pretreatment in PFC with the selective KOR antagonist norbinaltorphimine (norBNI) blocked the disruptive effect of systemic KOR activation during both early and late phases of the session. The early, but not late phase disruption was blocked by viral excision of PFC KORs, suggesting an anatomically dissociable contribution of pre- and postsynaptic KORs. Naloxone-precipitated withdrawal in morphine-dependent mice or optical stimulation of pdynCre neurons using Channelrhodopsin-2 (ChR2) disrupted delayed alternation performance, and the dynorphin-induced effect was blocked by local norBNI. Our findings describe a mechanism for control of cortical function during opioid dependence and suggest that KOR antagonism could promote abstinence.

Download Full-text

Muscarinic acetylcholine neurotransmission enhances the late-phase of long-term potentiation in the hippocampal–prefrontal cortex pathway of rats in vivo: A possible involvement of monoaminergic systems

Neuroscience ◽

10.1016/j.neuroscience.2008.02.040 ◽

2008 ◽

Vol 153 (4) ◽

pp. 1309-1319 ◽

Cited By ~ 26

Author(s):

C. Lopes Aguiar ◽

R. Neves Romcy-Pereira ◽

R. Escorsim Szawka ◽

O. Yineth Galvis-Alonso ◽

J. Aparecida Anselmo-Franci ◽

...

Keyword(s):

Prefrontal Cortex ◽

Late Phase ◽

Long Term Potentiation ◽

Muscarinic Acetylcholine ◽

Term Potentiation

Download Full-text

High-Resolution 7T MR Imaging of the Human Subgenual Prefrontal Cortex in vivo- Development of a segmentation algorithm and its application in mood disorders

Klinische Neurophysiologie ◽

10.1055/s-0033-1337207 ◽

2013 ◽

Vol 44 (01) ◽

Author(s):

A Tränkner ◽

P Schönknecht

Keyword(s):

Prefrontal Cortex ◽

High Resolution ◽

Mr Imaging ◽

Mood Disorders ◽

Segmentation Algorithm

Download Full-text

Faculty Opinions recommendation of Synaptic basis of persistent activity in prefrontal cortex in vivo and in organotypic cultures.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016066.199621 ◽

2003 ◽

Author(s):

Jan-Marino Ramirez

Keyword(s):

Prefrontal Cortex ◽

Persistent Activity ◽

Organotypic Cultures

Download Full-text

Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

Molecular Psychiatry ◽

10.1038/s41380-021-01016-1 ◽

2021 ◽

Author(s):

Young-Min Han ◽

Min Sun Kim ◽

Juyeong Jo ◽

Daiha Shin ◽

Seung-Hae Kwon ◽

...

Keyword(s):

Inhibitory Action ◽

Time Course ◽

Molecular Mechanisms ◽

Late Phase ◽

Fine Tuning ◽

Dependent Manner ◽

Middle Phase ◽

Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

Download Full-text

High Natural Permissivity of Primary Rabbit Cells for HIV-1, with a Virion Infectivity Defect in Macrophages as the Final Replication Barrier

Journal of Virology ◽

10.1128/jvi.01607-10 ◽

2010 ◽

Vol 84 (23) ◽

pp. 12300-12314 ◽

Cited By ~ 14

Author(s):

Hanna-Mari Tervo ◽

Oliver T. Keppler

Keyword(s):

T Cells ◽

Late Phase ◽

Small Animal ◽

Receptor Complex ◽

Restriction Factors ◽

Cyclin T1 ◽

Primary Rabbit ◽

Species Specific ◽

Hiv 1

ABSTRACT An immunocompetent, permissive, small-animal model would be valuable for the study of human immunodeficiency virus type 1 (HIV-1) pathogenesis and for the testing of drug and vaccine candidates. However, the development of such a model has been hampered by the inability of primary rodent cells to efficiently support several steps of the HIV-1 replication cycle. Although transgenesis of the HIV receptor complex and human cyclin T1 have been beneficial, additional late-phase blocks prevent robust replication of HIV-1 in rodents and limit the range of in vivo applications. In this study, we explored the HIV-1 susceptibility of rabbit primary T cells and macrophages. Envelope-specific and coreceptor-dependent entry of HIV-1 was achieved by expressing human CD4 and CCR5. A block of HIV-1 DNA synthesis, likely mediated by TRIM5, was overcome by limited changes to the HIV-1 gag gene. Unlike with mice and rats, primary cells from rabbits supported the functions of the regulatory viral proteins Tat and Rev, Gag processing, and the release of HIV-1 particles at levels comparable to those in human cells. While HIV-1 produced by rabbit T cells was highly infectious, a macrophage-specific infectivity defect became manifest by a complex pattern of mutations in the viral genome, only part of which were deamination dependent. These results demonstrate a considerable natural HIV-1 permissivity of the rabbit species and suggest that receptor complex transgenesis combined with modifications in gag and possibly vif of HIV-1 to evade species-specific restriction factors might render lagomorphs fully permissive to infection by this pathogenic human lentivirus.

Download Full-text