The role of beta-catenin and the cadherin adhesion complex in synaptic plasticity, learning and addiction

A fundamental property of synapses is their ability to change in response to activity, termed ‘synaptic plasticity’. Synaptic activity can cause long-lasting increases in the strength of synapses (long-term potentiation, or ‘LTP’), as well as decreases in synapse strength (long-term depression or ‘LTD’), both of which are believed to be important for learning and memory. The synaptic adhesion molecules ‘cadherins’ and their intracellular binding partner β-catenin have been identified as key mediators of plasticity at synapses. The cadherin adhesion complex is important for maintaining the strength and stability of synapses, and disruption of cadherin function has been shown to impair long-term potentiation (LTP). However, it remains unclear how increases in cadherin adhesion can affect synaptic function and cognition. This is important in light of studies showing that increases in β-catenin levels and mutations in cadherin adhesion complex proteins are associated with many different neurodegenerative diseases, as well as psychiatric disorders such as drug abuse, raising the possibility that aberrant increases in cadherin adhesion may contribute to cognitive impairments in these disorders. In this dissertation, I examine the effects of increases in cadherin adhesion on different forms of synaptic plasticity in the brain. I demonstrate that increases in β-catenin in the hippocampus can stabilize cadherin at the synaptic membrane and abolish long-term depression (LTD) at synapses, leading to significant impairments in spatial memory flexibility and reversal learning. I also demonstrate a role for cadherin in activity- and drug-induced plasticity in the ventral tegmental area (VTA), a region of the brain important for reward learning which is implicated in addiction, and show that cocaine-mediated conditioned place preference results in redistribution of cadherin and AMPA receptors to excitatory synapses onto dopaminergic neurons in the VTA. Together, these results demonstrate that the β-catenin/cadherin adhesion complex plays an important role in several forms of learning and memory, and that aberrant increases in synaptic adhesion can have a detrimental effect on synaptic plasticity and cognitive function.Medicine, Faculty ofGraduat

Consumption of palatable food primes food approach behavior by rapidly increasing synaptic density in the VTA

Photograph of members of the Boley Mennonite community at a Saturday afternoon picnic

Thalamus sends information about arousal but not valence to the amygdala

Abstract Rationale The basolateral amygdala (BLA) and medial geniculate nucleus of the thalamus (MGN) have both been shown to be necessary for the formation of associative learning. While the role that the BLA plays in this process has long been emphasized, the MGN has been less well-studied and surrounded by debate regarding whether the relay of sensory information is active or passive. Objectives We seek to understand the role the MGN has within the thalamoamgydala circuit in the formation of associative learning. Methods Here, we use optogenetics and in vivo electrophysiological recordings to dissect the MGN-BLA circuit and explore the specific subpopulations for evidence of learning and synthesis of information that could impact downstream BLA encoding. We employ various machine learning techniques to investigate function within neural subpopulations. We introduce a novel method to investigate tonic changes across trial-by-trial structure, which offers an alternative approach to traditional trial-averaging techniques. Results We find that the MGN appears to encode arousal but not valence, unlike the BLA which encodes for both. We find that the MGN and the BLA appear to react differently to expected and unexpected outcomes; the BLA biased responses toward reward prediction error and the MGN focused on anticipated punishment. We uncover evidence of tonic changes by visualizing changes across trials during inter-trial intervals (baseline epochs) for a subset of cells. Conclusion We conclude that the MGN-BLA projector population acts as both filter and transferer of information by relaying information about the salience of cues to the amygdala, but these signals are not valence-specified

Cortical ensembles orchestrate social competition through hypothalamic outputs.

Most social species self-organize into dominance hierarchies1,2, which decreases aggression and conserves energy3,4, but it is not clear how individuals know their social rank. We have only begun to learn how the brain represents social rank5-9 and guides behaviour on the basis of this representation. The medial prefrontal cortex (mPFC) is involved in social dominance in rodents7,8 and humans10,11. Yet, precisely how the mPFC encodes relative social rank and which circuits mediate this computation is not known. We developed a social competition assay in which mice compete for rewards, as well as a computer vision tool (AlphaTracker) to track multiple, unmarked animals. A hidden Markov model combined with generalized linear models was able to decode social competition behaviour from mPFC ensemble activity. Population dynamics in the mPFC predicted social rank and competitive success. Finally, we demonstrate that mPFC cells that project to the lateral hypothalamus promote dominance behaviour during reward competition. Thus, we reveal a cortico-hypothalamic circuit by which the mPFC exerts top-down modulation of social dominance

Corticoamygdala Transfer of Socially Derived Information Gates Observational Learning

Observational learning is a powerful survival tool allowing individuals to learn about threat-predictive stimuli without directly experiencing the pairing of the predictive cue and punishment. This ability has been linked to the anterior cingulate cortex (ACC) and the basolateral amygdala (BLA). To investigate how information is encoded and transmitted through this circuit, we performed electrophysiological recordings in mice observing a demonstrator mouse undergo associative fear conditioning and found that BLA-projecting ACC (ACC→BLA) neurons preferentially encode socially derived aversive cue information. Inhibition of ACC→BLA alters real-time amygdala representation of the aversive cue during observational conditioning. Selective inhibition of the ACC→BLA projection impaired acquisition, but not expression, of observational fear conditioning. We show that information derived from observation about the aversive value of the cue is transmitted from the ACC to the BLA and that this routing of information is critically instructive for observational fear conditioning. Video Abstract: [Figure presented] For an individual to watch another's experience and learn from it, signals need to move from cortical neurons to the basolateral amygdala during detection and integration of the necessary social cues.NIMH (Grant R01-MH102441-01)NIA (Grant RF1-AG047661-01)NIDDK (Award DP2-DK-102256-01)NCCIH (Grant DP1-AT009925)NIH (Grants 1-R01-AG-050548-01, DP1-OD003646 and R01-GM104948

Regulation of dendritic spine growth through activity-dependent recruitment of the brain-enriched Na+/H+ exchanger NHE5

pH homeostasis in neurons plays crucial roles in normal synaptic functions. It is found that the Na+/H+ exchanger NHE5 is targeted to the synapse on neuronal activation, regulates the synaptic pH, and controls the morphology of dendritic spines