Nogo receptor 1 (NgR1) is expressed in forebrain neurons and mediates nerve growth inhibition in response to Nogo and other ligands. Neuronal activity downregulates NgR1 and the inability to downregulate NgR1 impairs long-term memory. We investigated behavior in a serial behavioral paradigm in mice that overexpress or lack NgR1, finding impaired locomotor behavior and recognition memory in mice lacking NgR1 and impaired sequential spatial learning in NgR1 overexpressing mice. We also investigated a role for NgR1 in drug-mediated sensitization and found that repeated cocaine exposure caused stronger locomotor responses but limited development of stereotypies in NgR1 overexpressing mice. This suggests that NgR1-regulated synaptic plasticity is needed to develop stereotypies. Ex vivo magnetic resonance imaging and diffusion tensor imaging analyses of NgR1 overexpressing brains did not reveal any major alterations. NgR1 overexpression resulted in significantly reduced density of mature spines and dendritic complexity. NgR1 overexpression also altered cocaine-induced effects on spine plasticity. Our results show that NgR1 is a negative regulator of both structural synaptic plasticity and dendritic complexity in a brain region-specific manner, and highlight anterior cingulate cortex as a key area for memory-related plasticity.

Mild traumatic brain injury (mTBI) constitutes 75 ∼ 90% of all TBI cases and causes various physical, cognitive, emotional, and other psychological symptoms. Nogo receptor 1 (NgR1) is a regulator of structural brain plasticity during development and in adulthood. Here, we used mice that, in the absence of doxycycline, overexpress NgR1 in forebrain neurons (MemoFlex) to determine the role of NgR1 in recovery from mTBI with respect to balance, cognition, memory, and emotion. We compared wild-type (WT), MemoFlex, and MemoFlex + doxycycline mice to the same three groups subjected to mTBI. mTBI was induced by a controlled 30-g weight drop. We found that inability to downregulate NgR1 significantly impairs recovery from mTBI-induced impairments. When the NgR1 transgene was turned off, recovery was similar to that of WT mice. The results suggest that the ability to regulate NgR1 signaling is needed for optimal recovery of motor coordination and balance, spatial memory, cognition, and emotional functions after mTBI.

Psilocybin is a psychedelic substance approaching clinical use. The drug has long-lasting effects after single or multiple administrations and enhances structural plasticity in the brain. Little is known if the plasticity inducing effects of psilocybin could be timed to other treatments and promote a larger effect. We investigated the effect of psilocybin on cultured mouse hippocampal neurons, examining the plasticity promoting effects from 5 min to 72 h post-treatment. We found robust effects on pre- and postsynaptic (Piccolo and Homer1) protein expression 1-3 h following treatment. Presynaptic Synapsin-1 expression mirrored these findings, with peak expression 72 h post-treatment. Our studies suggest psilocybin opens a window of plasticity that rapidly normalizes. As psilocybin has been shown to have an effect treating diseases (e.g. depression and cluster headache) linked with inflammation, we used an immortalized microglia cell line (IMG) to demonstrate its anti-inflammatory effects against a lipopolysaccharide (LPS) challenge (we show reduced tumor necrosis factor-alpha (TNF-α) secretion). Altogether, our studies show discrete and acute cell type specific effects of psilocybin that provides insight into its mechanisms of action and potential therapeutic value.

Structural synaptic reorganizations needed to permanently embed novel memories in the brain involve complex plasticity-enhancing and plasticity-inhibiting systems. Increased neural activity is linked to rapid downregulation of Nogo receptor 1 (NgR1), needed to allow local structural synaptic plasticity. This local regulation of plasticity is thought to be moderated by global systems, such as the ascending cholinergic and monoaminergic systems, adding significance to locally increased neural activity. Here we address the reverse possibility that the global systems may also be influenced by the status of local plasticity. Using NgR1-overexpressing mice, with impaired plasticity and long-term memory, we measured the ability to release dopamine (DA), implicated in regulating plasticity and memory. In vivo chronoamperometric recording with high temporal and spatial resolution revealed severe impairment of potassium chloride (KCl)-induced increase of extracellular DA in the dorsal striatum of mice overexpressing NgR1 in forebrain neurons. A similar, but lesser, impairment of DA release was seen following amphetamine delivery. In contrast, potassium chloride-evoked DA release in NgR1 knockout (KO) mice led to increased levels of extracellular DA. That NgR1 can impair DA signaling, thereby further dampening synaptic plasticity, suggests a new role for NgR1 signaling, acting in synergy with DA signaling to control synaptic plasticity.Significance Statement:The inverse correlation between local NgR1 levels and magnitude of KCl-inducible amounts of DA release in the striatum reinforces the rule of NgR1 as a regulator of structural synaptic plasticity and suggests synergy between local and global plasticity regulating systems.

Sleep is essential for long term memory function. However, the neuroanatomical consequences of sleep loss are disputed. Sleep deprivation has been reported to cause both decreases and increases of dendritic spine density. Here we use Thy1-GFP expressing transgenic mice to investigate the effects of acute sleep deprivation on the dendritic architecture of hippocampal CA1 pyramidal neurons. We found that 5 h of sleep deprivation had no effect on either dendritic length or dendritic spine density. Our work suggests that no major neuroanatomical changes result from a single episode of sleep deprivation.