Kwok, L. | Search bioRxiv

bioRxiv2026

LSD persistently disrupts affective pain processing

Psychedelics produce long-lasting effects, but their circuit mechanisms remain unclear. Here we show that, in rats, a single dose of lysergic acid diethylamide (LSD) persistently reduces pain affect. This effect is recapitulated by local administration in the anterior cingulate cortex (ACC), but not primary somatosensory cortex. Neuropixels recordings reveal that LSD suppresses stimulus-evoked nociceptive responses in the ACC, reducing the encoding of aversive value. Despite increasing intrinsic excitability ex vivo, LSD reduces the maximum stimulus-evoked firing of ACC neurons in vivo, indicating a dissociation between excitability and sensory encoding. Together, these findings show that psychedelics disrupt the cortical transformation of nociceptive input into aversive representations.

neuroscience↗

bioRxiv2025

PKMζ-PKC{iota}/{lambda} double-knockout reveals the atypical PKCs are crucial for hippocampal late-LTP and spatial long-term memory

PKM{zeta}, a persistently active atypical PKC (aPKC) isoform, is thought to maintain late-phase long-term potentiation (late-LTP) and long-term memory. However, PKM{zeta}-knockout mice still exhibit hippocampal LTP and spatial memory while lacking neocortical LTP, questioning whether this kinase is fundamental to enduring synaptic potentiation and memory. Tsokas et al. (2016) showed the other aPKC, PKC{iota}/{lambda}, likely compensates for PKM{zeta} during maintenance in the hippocampus of PKM{zeta}-null mice. In wild-type mice, PKC{iota}/{lambda} drives early-LTP and short-term memory, while PKM{zeta} compensates for PKC{iota}/{lambda} knockout by supporting both early- and late-phase processes. Here we show PKC{iota}/{lambda} persistently increases during maintenance in two mouse models: PKM{zeta}-conditional knockout (cKO) mice, and double-knockout mice carrying both conditional deletion of PKC{iota}/{lambda} and constitutive loss of PKM{zeta}. In the double-knockout mice, PKC{iota}/{lambda} was measured while the kinase was still present, prior to its inducible ablation, to characterize its compensatory upregulation in late-LTP before removal. To test whether this compensation was functional, we ablated PKC{iota}/{lambda} in the hippocampus of the double-knockout mice. The double-knockout eliminated late-LTP, whereas individual knockout of either aPKC alone showed normal-appearing LTP. Double-knockout also abolished spatial long-term memory without affecting short-term memory. Thus, when PKM{zeta} is absent, PKC{iota}/{lambda} persists to maintain hippocampal late-LTP and long-term memory.

neuroscience↗