Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice

Abstract

Background: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive. Methods: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose–response effects of cumulative LSD doses (5–160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex. Results: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose–response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex. Conclusion: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

Bridging the Gap? Altered Thalamocortical Connectivity in Psychotic and Psychedelic States

“…We speculate that the stability of the thalamocortical dysconnectivity patterns observed in psychosis (i.e., across the stages of psychosis, persistence despite treatment with antipsychotic medication) is grounded in the substantial disorganization of the thalamocortical system. In contrast, thalamocortical dysconnectivity in psychedelic states is not only transient, but can be blocked by ketanserin (28) and perhaps antipsychotics (26).…”

“…The left side shows the impaired thalamic filter function induced by psychedelic stimulation of 5-HT 2A receptors, which leads to increased extracellular glutamate levels in the prefrontal cortex and inhibitory activity of interneurons in the basal ganglia, thereby increasing the excitatory effect of pyramidal neurons both on the basal ganglia (depicted by the thick unidirectional red arrow between the cerebral cortex and the striatum) and the thalamus (depicted by the thick bidirectional red arrow between the cerebral cortex and the thalamus) (24,25). Recent evidence also indicates that psychedelics (i.e., LSD) modulate activity in the reticular thalamus leading to the disinhibition of other thalamic nuclei (i.e., mediodorsal nucleus-not shown) (26). In parallel, the increased striatal activity leads to a similar chain of events as seen in psychotic states (i.e., also resulting in enhanced thalamic disinhibition) (18).…”

“…In line with this idea, psychedelics might also induce thalamocortical hyperconnectivity via effects elicited directly on the thalamus. Inserra et al (26) found that LSD modulates neurons of the reticular thalamus in mice, which in turn disinhibits the mediodorsal nucleus. Such disinhibition of higher-order nuclei might very well be associated with increased thalamocortical interaction (indeed, an increase in the firing of prefrontal pyramidal neurons was also observed), possibly corresponding to thalamocortical hyperconnectivity.…”

“…Such disinhibition of higher-order nuclei might very well be associated with increased thalamocortical interaction (indeed, an increase in the firing of prefrontal pyramidal neurons was also observed), possibly corresponding to thalamocortical hyperconnectivity. Interestingly, Inserra et al (26) suggest that the LSD-induced disinhibition of the mediodorsal nucleus was mediated by dopaminergic transmission (i.e., the effect was reversed by antipsychotics). This might be in contrast to the findings in humans, as antipsychotic medication does not appear to normalize thalamocortical dysconnectivity in patients with schizophrenia (55).…”

Serotonergic Psychedelics in Neural Plasticity

“…Despite the long-standing interest in LSD's cognitive effects, its cellular impact has only been explored recently. On the neural circuit level, LSD can modulate the spontaneous firing and burst-firing of reticular thalamus GABAergic neurons and disinhibit thalamocortical relay neurons in the mediodorsal thalamus in mice, as shown by in vivo electrophysiology (Inserra et al, 2021b). At the sub-cellular level, one study (Ly et al, 2018) on cultured rat cortical neurons found that 24 h LSD treatment significantly increases dendritic arbor complexity and dendritic spine density.…”