Does Toxoplasma gondii infection have a causal impact on human psychopathology? A Mendelian randomization analysis.

Pain is transmitted from the periphery to the brain through several key central relays including the spinal cord dorsal horn and thalamus. After periphery injuries such as inflammation or nerve injury, it is well known that glutamatergic synapses in the spinal cord including spinothalamic tract (STT) cells are sensitized or undergo long-term potentiation (LTP). The anterior cingulate cortex (ACC) plays critical roles in pain perception and related emotional responses. Human imaging and in vivo electrophysiological recordings of animal ACC neurons show that neurons in the ACC are activated by noxious sensory stimuli, and inhibiting central plasticity in the ACC produces analgesic effects in different animal models of chronic pain. Synaptic plasticity, LTP, is critical for memory, fear and chronic pain. Cumulative evidence suggests that ACC synapses are highly plastic. Two major forms of LTPs have been found in the ACC: pre-LTP and post-LTP in vitro. Post-LTP in the ACC is typically induced by theta burst stimulation (TBS). The activation of postsynaptic NMDA receptors is critical for the induction of post-LTP, while postsynaptic modification of AMPA receptor contribute to the expression of post-LTP. Behavioral and genetic studies suggest that post-LTP preferentially contribute to behavioral sensitization after peripheral injury, pre-LTP contributes injury-related anxiety. It is generally believed that ACC neurons receive peripheral sensory information through thalamus-ACC projections as well as indirect projections from somatosensory cortices. In addition, recent studies reveal that ACC neurons also receive projections from hippocampus, amygdala, and other subcortical areas. Due to the limitation of focal electrical stimulation, previous studies did not distinguish the selective input source in vitro brain slice and in vivo electrophysiological experiments. Furthermore, few studies of ACC LTP is recorded from freely moving animals. Thalamus is a key relay nucleus for transferring spinal nociceptive information to various cortical regions (by STT cells). The projection from the thalamus to the ACC have been well documented in different species, and it is believed to be major nociceptive inputs to the ACC, in addition to cortical projections from somatosensory cortice. Electrophysiological experiments using thalamic stimulation in adult rats have confirmed the existence of thalamic-anterior cingulate projections. Electrical stimulation of mediodorsal (MD), midline, and intralaminar thalamic nuclei induced short-term plastic changes in layers II/III of the ACC that transmit nociceptive information to the ACC in early stage of chronic pain. However, there is no report of LTP in these studies. Recently in adult mice we have investigated the projection to ACC and showed direct monosynaptic glutamatergic connections from the thalamus to ACC pyramidal cells in vitro by using optogenetic stimulation.