The endocannabinoid system and cognition

THC-treatment differentially alters spines dynamics in old and young mice The endocannabinoid system (ECS) is a neuromodulatory system involved in cognitive processes. Increasing the ECS tone with low-dosage THC - a potent agonist of two main cannabinoid receptors (CB1R and CB2R) – has been shown to restore the diminished cognitive abilities of old mice back to the levels of young mice. In contrast, the same treatment in young mice had an opposite or no effect. In old mice, changes in cognition were accompanied by altered gene expression profile. Among others, upregulation of genes encoding synaptic proteins. Thus, pending the question how does THC treatment influences synapses and their dynamics. We examined the effects of chronic low-dose THC treatment on synapses by following up on the same dendritic spines before, during, and after the THC treatment using in vivo chronic imaging in 3-month and 18-month old mice. Subsequently, in 18-month old animals we investigated THC-evoked changes in microglia activity as a possible mechanism behind observed changes in the spine dynamics. We found that the timing and direction of the THC effect was age-dependent. In 18-month old mice, THC treatment increased spine density and spine stability, while decreasing spine dynamics. Investigation of microglia activity revealed that THC treatment decreased microglia phagocytic activity and contacts between microglia and neurons. In contrast, in 3-month old mice THC treatment only temporarily increased spine dynamics and thus decreased spine stability. Taken together, our investigations indicate that THC treatment differentially alters spine dynamics in young and old mice possibly through the modulation of microglial activity. Cannabinoid receptor 2 and cognition Although the cannabinoid receptor 2 (CB2R) is often thought to play a role mainly outside the brain, several publications have comfirem the presence of CB2R on hippocampal principal neurons. Activation of CB2R produces a long-lasting membrane potential hyperpolarization, alters the input/output function of CA2/3 principal neurons and produces alterations in gamma oscillations. However, other cellular, molecular and behavioral consequences of hippocampal CB2R signaling have not been studied in detail. Here, we investigated the role of CB2R in cognition in two different aspects. First, we focused on age-related changes in the CB2R knockout mice (CB2R-/-) using a series of behavioural paradigms testing memory and anxiety-like behaviour. Second, we investigated gender-specific alterations in CB2R-/- mice in the context of social memory and synaptic architecture using immunohistochemical stainings of synaptic proteins. Our investigation covered synapsin-I, vesicular GABA transporter (vGAT) and vesicular glutamate transporter (vGLUT1). We found that CB2R-/- mice had only a minor age-dependent alteration in social memory. In the partner recognition task, 3-month and 12-month old mice performed worse and 18-month old mice preformed better than their age-matched controls. At the same time, we noticed that CB2R-/- mice exhibited an age-independent decrease in anxiety-like behaviours. Furthermore, we found that the deletion of CB2R lead to increased synapsin-I signal and particle density, as well as increased vGAT signal in the hippocampus. This phenotype was restricted to females. We confirmed an impairment of social memory in 6-month old CB2R deficient mice, observed in both genders. Our results thus demonstrate that the lack of CB2R leads to changes in the hippocampal synaptic landscape and reveals an important gender-specific difference in endocannabinoid signaling. Our studies support a significant role of the CB2R in modulation of different types of memory despite its low expression levels in the brain and provides more insight into a gender-specific role of CB2R in synaptic architecture

CB2 Receptor in Microglia: The Guardian of Self-Control

Microglia are key to maintaining the homeostasis of the brain. These immune cells of the brain can be our biggest ally in fighting infections, but can worsen pathology or hinder recovery when uncontrolled. Thus, understanding how microglia contribute to neuroinflammatory processes and how their activity can be controlled is of great importance. It is known that activation of endocannabinoid system, and especially the cannabinoid type 2 receptor (CB2R), decreases inflammation. Alongside its non-psychoactive effect, it makes the CB2R receptor a perfect target for treating diseases accompanied by neuroinflammation including neurodegenerative diseases. However, the exact mechanisms by which CB2R regulates microglial activity are not yet understood. Here, we review the current knowledge on the roles of microglial CB2R from in vitro and in vivo studies. We look into CB2R function under physiological and pathological conditions and focus on four different disease models representing chronic and acute inflammation. We highlight open questions and controversies and provide an update on the latest discoveries that were enabled by the development of novel technologies. Also, we discuss the recent findings on the role of microglia CB2R in cognition and its role in neuron–microglia communication

Cannabinoid Receptor 2 Alters Social Memory and Microglial Activity in an Age-Dependent Manner

Physiological brain aging is characterized by gradual, substantial changes in cognitive ability, accompanied by chronic activation of the neural immune system. This form of inflammation, termed inflammaging, in the central nervous system is primarily enacted through microglia, the resident immune cells. The endocannabinoid system, and particularly the cannabinoid receptor 2 (CB2R), is a major regulator of the activity of microglia and is upregulated under inflammatory conditions. Here, we elucidated the role of the CB2R in physiological brain aging. We used CB2R−/− mice of progressive ages in a behavioral test battery to assess social and spatial learning and memory. This was followed by detailed immunohistochemical analysis of microglial activity and morphology, and of the expression of pro-inflammatory cytokines in the hippocampus. CB2R deletion decreased social memory in young mice, but did not affect spatial memory. In fact, old CB2R−/− mice had a slightly improved social memory, whereas in WT mice we detected an age-related cognitive decline. On a cellular level, CB2R deletion increased lipofuscin accumulation in microglia, but not in neurons. CB2R−/− microglia showed an increase of activity markers Iba1 and CD68, and minor upregulation in tnfa and il6 expression and downregulation of ccl2 with age. This was accompanied by a change in morphology as CB2R−/− microglia had smaller somas and lower polarity, with increased branching, cell volume, and tree length. We present that CB2Rs are involved in cognition and age-induced microglial activity, but may also be important for microglial activation itself

Transient sensorimotor projections in the developmental song learning period

Summary: Memory recall and guidance are essential for motor skill acquisition. Like humans learning to speak, male zebra finches learn to sing by first memorizing and then matching their vocalization to the tutor’s song (TS) during specific developmental periods. Yet, the neuroanatomical substrate supporting auditory-memory-guided sensorimotor learning has remained elusive. Here, using a whole-brain connectome analysis with activity-dependent viral expression, we identified a transient projection into the motor region, HVC, from neuronal ensembles responding to TS in the auditory forebrain, the caudomedial nidopallium (NCM), in juveniles. Virally induced cell death of the juvenile, but not adult, TS-responsive NCM neurons impaired song learning. Moreover, isolation, which delays closure of the sensory, but not the motor, learning period, did not affect the decrease of projections into the HVC from the NCM TS-responsive neurons after the song learning period. Taken together, our results suggest that dynamic axonal pruning may regulate timely auditory-memory-guided vocal learning during development