While cognitive processing and memory consolidation occur during both sleep and wake, each sleep state serves an individual and unique role in these processes. Rapid-eye movement (REM) sleep, for instance, is critical for associative learning, in which two unrelated stimuli become cognitively linked. The neurotransmitter norepinephrine (NE) is released throughout wakefulness but is especially abundant during learning and stress. Indeed, NE is believed to play a major role in traditional Hebbian plasticity during memory consolidation, which is guided by the process of long-term potentiation (LTP) where individual synaptic connections between associated neurons strengthen with repeated firing. LTP in the hippocampus is physiologically responsible for associative learning and memory. When presented with new information during reversal learning, reconfiguring memories requires the opposite of LTP, depotentiation (LTD), in order to weaken existing synaptic connections and integrate this new information into learning schema. The presence of NE promotes synaptic strengthening, so LC silence during REM provides a unique neurochemical environment that allows for LTD in normally functioning organisms. However, different neurological or psychiatric pathologies result in aberrant LC activity during REM sleep, resulting in maladaptive changes to the processes of learning, memory, and forgetting.

The ability of an organism to survive often rests on the degree to which it is able to learn about its environment, separate useful information from noise, and file it away to be rapidly recalled at the appropriate time. For animals in the wild, this often amounts to recalling where food is buried, or what to do to avoid capture when a hawk flies overhead. For humans, our ability to retain and access memories over the years is arguably the crux of what it means to have a sense of self and form a cohesive narrative of our lives. Indeed, some of the most devastating psychiatric and neurological disorders strike directly at this ability. Alzheimer’s disease and other dementias rob individuals of past experiences that form the fabric of their lives and personalities; psychiatric disorders such as schizophrenia dampen a person’s mental acuity and flexibility, as well as the ability to distinguish between important and unimportant information. Ultimately, understanding how memories are encoded and stably stored through time is an important window through which we can better understand the things that make us who we are, and the consequences that occur when this process is disrupted. As such, interrogating the mechanisms underlying memory formation and storage is one of the most pressing topics in neuroscience at the moment. In chapter 1 of this dissertation, I will provide a discussion of concepts foundational to the study of learning and memory, aiming to describe the multiple scales across which neuroscientists study the formation and storage of information, from molecular mechanisms, cellular physiology, synaptic connections, and network activity. I will also discuss the unique aspects of hippocampal anatomy, cellular composition and physiology that have evolved to position this structure as the initial locus of memory traces. Chapter 2 discusses the role of sleep in memory consolidation, aiming to describe the importance of each sleep stage and their unique physiology on facilitating strengthening and storing the labile memory traces formed during waking. In particular, I focus on what modern approaches allowing us to selectively modulate the activity of neural subsets can tell us about the circuit and cellular mechanisms underlying offline consolidation, which may have been obscured by methodological constraints in earlier sleep research. In chapter 3, I describe experiments that investigate the role of a subpopulation of hippocampal interneurons, oriens-lacunosum moleculare (OLM) cells, in promoting sleep-dependent memory consolidation. By inhibiting this cell population selectively during offline periods between task acquisition and recall, we found that OLM cells in the hippocampus are necessary for offline spatial and contextual memory consolidation. Through in vivo recordings of brain activity with and without OLM inhibition, we linked this cell population to oscillatory activity during rapid eye movement (REM) sleep periods. These experiments are among the first to posit a role for OLM cells in sleep-dependent consolidation and provide further evidence for the necessity of sleep to the formation of and maintenance of memories.

Ubiquitination of a target protein is an important post-translational modification. There is evidence for the involvement of ubiquitination of presynaptic proteins in synaptic transmission. Vesicle associated membrane protein (VAMP2) is a presynaptic protein that is fundamental for vesicle docking and fusion and here we test the hypothesis that ubiquitination of VAMP2 is important for synaptic transmission. To test this hypothesis, we downregulated expression of endogenous VAMP2 and allowed for the expression of mutant VAMP2 that cannot undergo ubiquitination. Using electrophysiological recordings in cortical neuronal cultures from autapses (synapses made by a neuron onto itself), we found that knocking down endogenous VAMP2 reduces synaptic transmission and this is rescued with exogenous VAMP2. Our findings indicate that E1 inhibition alters synaptic transmission in control neurons, but not in neurons rescued with mutant VAMP2 with a knock down background. Our findings support our hypothesis that ubiquitination of VAMP2 modulates synaptic transmission.