Activity dependent transcriptional pathways underlying synaptic mechanisms for memory discrimination & generalization
- PI: Yingxi Lin
- The ability of the brain to utilize information from past experiences to guide future decisions, termed adaptive behavior, is critical for survival. To effectively adapt behaviors, the brain applies stored memory to new but similar situations (generalization), while also maintaining the capacity to distinguish unique stimuli (discrimination). When these critical processes (memory generalization or discrimination) go awry, it can lead to maladaptive disorders such as post-traumatic stress disorder (PTSD) and panic disorder. Despite their importance, mechanisms underlying memory discrimination and generalization remain largely unknown. This proposal will investigate the dynamic processes that underlie the utilization of an encoded memory to guide future behaviors, in particular the molecular, synaptic, and circuit mechanisms that govern the balance between discrimination and generalization.
Synaptic Mechanisms for Contextual Memory Formation
- PI: Yingxi Lin
- Learning and memory defines how animals interact with their environment. This process relies on experience-driven changes in synaptic connections, a phenomenon known as synaptic plasticity; disruption of this process is believed to underlie several cognitive and psychiatric disorders. Although synaptic plasticity is critical for learning and memory, the mechanisms by which memory is formed and stored in neural circuits remains poorly understood. The proposed studies address this knowledge gap by focusing on synaptic mechanisms by which contextual memory is encoded in CA3 pyramidal neurons of the hippocampus, a brain region with a central role in learning and memory. Among the excitatory inputs converging onto CA3 pyramidal neurons, the mossy fiber (MF) input from dentate gyrus granule cells is known to be required for the encoding of contextual memory. Using genetic tools recently developed by us, we were able to identify the specific group of CA3 neurons activated by contextual learning, and identified a learning-dependent synaptic modification associated with these neurons.
How does the brain capture transient sensory experience and convert it into long lasting changes in neural circuits?
This is one of the outstanding questions in modern neuroscience, and it is the central question that drives the research in the Lin Lab. Understanding the underlying mechanism will be key to our understanding of how the brain works and of how to restore normal function in diseased brains.
The research team in the Lin Lab use multi-disciplinary approaches to address our research questions. We carry out studies using various experimental paradigms in rodents, ranging from primary neuron cultures, through acute and cultured brain slices, to whole animal behavioral analysis. Our studies employ a combination of molecular, genetic, imaging, electrophysiological, optogenetic and animal behavioural techniques.
The following lists some of the active research areas in the Lin Lab:
- New gene transcription is required for neural circuits to capture transient experience and convert it into the long-lasting changes in neural circuits that underlie learning and memory. Neuronal activity-regulated gene transcription is essential for orchestrating the gene expression programs that drive experience-dependent plasticity of neural circuits. We are actively investigating transcription pathways that play important roles in coupling experience to the modification of neural circuits. The pathways that are critically altered in neuropsychiatric disorders are of particular interest to us, as they are likely to provide insights into the disease etiology.
- Like a conventional electrical circuit, neural circuits use both positive and negative components to amplify desirable signals while maintaining the overall stability of the system. We want to understand how this balance between excitation and inhibition is established during development and then maintained throughout life. The underlying molecular mechanisms are not well understood, but inhibitory neurons and their synaptic connections, which are readily modified by activity, are likely to play a critical role. We use molecular, genetic, and electrophysiological methods to understand how inhibitory circuits form within the brain, and how they are shaped by activity and experience. Impaired inhibition has been implicated in many brain disorders, including epilepsy, anxiety disorders, schizophrenia and autism. Having a better understanding of the brain's inhibitory circuits may shed light on the origins and possible treatments of these diseases.
- Each experience activates a unique set of neurons within specific regions of the brain. While we know the brain regions that are associated with particular types of sensory experience in many cases, we know very little about the identity of specific ensembles of neurons that are responsible for the encoding of specific sensory information, let alone the underlying molecular and cellular mechanisms. To fill this gap in our knowledge, we are developing tools that allow for the identification and manipulation of ensemble of neurons as they participate in the processing of sensory information. We have used some of the tools we have developed to address fundamental questions, such as: What determines which neurons are recruited to encode memory? How are these ensembles connected to other parts of the brain to influence behaviors? What synaptic changes have to happen in the ensemble to allow long term memory formation? What genes in the ensemble are essential for memory formation?