Papers by Sheena Josselyn
ABSTRACTToxoplasma gondii is a single celled parasite thought to infect 1 in 3 worldwide. During ... more ABSTRACTToxoplasma gondii is a single celled parasite thought to infect 1 in 3 worldwide. During chronic infection, T. gondii can migrate to the brain where it promotes low-grade neuroinflammation with the capacity to induce changes in brain morphology and behavior. Consequently, infection with T. gondii has been linked with a number of neurocognitive disorders including schizophrenia (SZ), dementia, and Parkinson’s disease. Beyond neuroinflammation, infection with T. gondii can modulate the production of neurotransmitters, such as dopamine. To further dissect these pathways and examine the impact of altered dopaminergic sensitivity in T. gondii-infected mice on both behavior and gene expression, we developed a novel mouse model, based on stimulant-induced (cocaine) hyperactivity. Employing this model, we found that infection with T. gondii did not alter fear behavior but did impact motor activity and neuropsychiatric-related behaviurs. While both behaviors may help reduce predator ...
Neuropsychopharmacology, 2019
The internal representation of an experience is thought to be encoded by long-lasting physical ch... more The internal representation of an experience is thought to be encoded by long-lasting physical changes to the brain ("engrams"). Previously, we and others showed within the lateral amygdala (LA), a region critical for auditory conditioned fear, eligible neurons compete against one other for allocation to an engram. Neurons with relatively higher function of the transcription factor CREB were more likely to be allocated to the engram. In these studies, though, CREB function was artificially increased for several days before training. Precisely when increased CREB function is important for allocation remains an unanswered question. Here, we took advantage of a novel optogenetic tool (opto-DN-CREB) to gain spatial and temporal control of CREB function in freely behaving mice. We found increasing CREB function in a small, random population of LA principal neurons in the minutes, but not 24 h, before training was sufficient to enhance memory, likely because these neurons were preferentially allocated to the underlying engram. However, similarly increasing CREB activity in a small population of random LA neurons immediately after training disrupted subsequent memory retrieval, likely by disrupting the precise spatial and temporal patterns of offline post-training neuronal activity and/or function required for consolidation. These findings reveal the importance of the timing of CREB activity in regulating allocation and subsequent memory retrieval, and further, highlight the potential of optogenetic approaches to control protein function with temporal specificity in behaving animals.
Neuropsychopharmacology, 2017
The formation of long-lasting memories requires coordinated changes in gene expression and protei... more The formation of long-lasting memories requires coordinated changes in gene expression and protein synthesis. Although many studies implicate DNA modifications (DNA methylation, histone modifications) in memory formation, the contributions of RNA modifications remain largely unexplored. Here we investigated the role of mRNA methylation in hippocampal-dependent memory formation in mice. RNA modifications are highly dynamic and readily reversible. Methyltransferases add a methyl group to mRNA while demethylases remove methyl groups. Here we focused on examining the role of the best characterized RNA demethylase, FTO (fat mass and obesityassociated) in memory. We observed that FTO is expressed in the nuclei, dendrites and near dendritic spines of mouse dorsal hippocampal CA1 neurons. Next, we found that contextual fear conditioning transiently (0.5 h) decreased Fto levels in these neurons, with the largest decrease in FTO observed near synapses. The decrease in FTO observed shortly after contextual fear conditioning suggests that FTO normally constrains memory formation. To directly test this, we artificially decreased FTO levels in dorsal hippocampus of otherwise normal (wild-type) mice by microinjecting before training a single herpes simplex virus (HSV) vector expressing either CRISPR/Cas9 or shRNA targeted against Fto. Decreasing FTO using either method specifically enhanced contextual fear memory. Together, these results show the importance of FTO during memory formation and, furthermore, implicate mRNA modification and epi-transcriptomics as novel regulators of memory formation.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 25, 2017
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cogniti... more Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Deep brain stimulation (DBS) has been used to treat a variety of brain disorders and shows promise in alleviating cognitive symptoms in some AD patients (Laxton et al., 2010). We previously showed that DBS of the entorhinal cortex (EC) enhances spatial memory formation in normal (wild-type) mice (Stone et al., 2011). Here we tested the effects of EC-DBS on the progressive cognitive deficits in a genetically-based mouse model of AD. TgCRND8 (Tg) transgenic mice express human amyloid precursor protein harboring the Swedish and Indiana familial AD mutations. These mice exhibit age-related increases in Aβ production, plaque deposition, as well as contextual fear and spatial memory impairments. Here, we found EC stimulation in young mice (6 weeks old) rescued the early contextual fear and spatial memory deficits and decreased subsequent plaque load in Tg mice. Moreover, stimulatio...
Neuropsychopharmacology, 2016
novel target for antidepressant drugs and offers a new strategy for treatment of depression. Take... more novel target for antidepressant drugs and offers a new strategy for treatment of depression. Taken together, GPCR heteroreceptor complexes and their receptorreceptor interactions represent a new fundamental principle in molecular medicine for integration of transmitter signals in the plasma membrane. A novel understanding of the molecular basis of CNS diseases is given together with new strategies for their treatment by targeting heteroreceptor complexes based on a new pharmacology with combined treatment, multi-targeted drugs and heterobivalent drugs. Our perspective on the future of research on heteroreceptor complexes is the further development and employment of multiple techniques for use in cellular models, brain tissue and in vivo studies to understand their role in discrete brain circuits. The advancement of the proximity ligation assay will be of special importance as will be the development of selective heterobivalent compounds for the heterocomplexes.
Proceedings of the National Academy of Sciences of the United States of America, Jan 17, 2011
Remodeling of cortical connectivity is thought to allow initially hippocampus-dependent memories ... more Remodeling of cortical connectivity is thought to allow initially hippocampus-dependent memories to be expressed independently of the hippocampus at remote time points. Consistent with this, consolidation of a contextual fear memory is associated with dendritic spine growth in neurons of the anterior cingulate cortex (aCC). To directly test whether such cortical structural remodeling is necessary for memory consolidation, we disrupted spine growth in the aCC at different times following contextual fear conditioning in mice. We took advantage of previous studies showing that the transcription factor myocyte enhancer factor 2 (MEF2) negatively regulates spinogenesis both in vitro and in vivo. We found that increasing MEF2-dependent transcription in the aCC during a critical posttraining window (but not at later time points) blocked both the consolidation-associated dendritic spine growth and subsequent memory expression. Together, these data strengthen the causal link between cortical...
Hippocampus, 2004
Much attention has been paid to the associative processes that are necessary to fuse together rep... more Much attention has been paid to the associative processes that are necessary to fuse together representations of the various components of an episodic memory. In the present study, we focus on the processes involved in the formation of lasting representations of the individual components that make up a fear-conditioning episode. In onetrial contextual fear conditioning experiments, weak conditioning to context occurs if the shock is delivered immediately following placement of the animal in a novel conditioning apparatus, a phenomenon known as the immediate shock deficit. We show that the immediate shock deficit in mice may be alleviated by pre-exposure to either the context or shock. In using this approach to temporally dissect a contextual fear-conditioning task into its constituent representational and associative processes, we are able to examine directly the processes that are important for formation of lasting representations of the context conditioned stimulus (CS) or unconditioned stimulus (US). Our data indicate that the formation of a lasting representation of the context or shock engages protein synthesis-dependent processes. Furthermore, genetic disruption of cAMP-responsive element binding protein (CREB), a transcription factor that regulates the synthesis of new proteins required for long-term memory, disrupts the formation of lasting context memories. We go on to show that the stress hormone epinephrine modulates the consolidation of a context memory, and reverses consolidation deficits in the CREB-deficient mice. Finally we show that disrupting either NMDA or calcium/calmodulin-dependent kinase II (CaMKII) function impairs consolidation of context memories. Together, these data suggest that this approach is particularly suited for the characterization of molecular and cellular processes underlying the formation of stimulus representations.
Science, 2007
Competition between neurons is necessary for refining neural circuits during development and may ... more Competition between neurons is necessary for refining neural circuits during development and may be important for selecting the neurons that participate in encoding memories in the adult brain. To examine neuronal competition during memory formation, we conducted experiments with mice in which we manipulated the function of CREB (adenosine 3′,5′-monophosphate response element–binding protein) in subsets of neurons. Changes in CREB function influenced the probability that individual lateral amygdala neurons were recruited into a fear memory trace. Our results suggest a competitive model underlying memory formation, in which eligible neurons are selected to participate in a memory trace as a function of their relative CREB activity at the time of learning.
Learning & Memory, 2000
In Pavlovian fear conditioning, a conditional stimulus (CS, usually a tone) is paired with an ave... more In Pavlovian fear conditioning, a conditional stimulus (CS, usually a tone) is paired with an aversive unconditional stimulus (US, usually a foot shock) in a novel context. After even a single pairing, the animal comes to exhibit a long-lasting fear to the CS and the conditioning context, which can be measured as freezing, an adaptive defense reaction in mice. Both context and tone conditioning depend on the integrity of the amygdala, and context conditioning further depends on the hippocampus. The reliability and efficiency of the fear conditioning assay makes it an excellent candidate for the screening of learning and memory deficits in mutant mice. One obstacle is that freezing in mice has been accurately quantified only by human observers, using a tedious method that can be subject to bias. In the present study we generated a simple, high-speed, and highly accurate algorithm that scores freezing of four mice simultaneously using NIH Image on an ordinary Macintosh computer. The a...
Learning & Memory, 2010
Although the transcription factor CREB has been widely implicated in memory, whether it is suffic... more Although the transcription factor CREB has been widely implicated in memory, whether it is sufficient to produce spatial memory under conditions that do not normally support memory formation in mammals is unknown. We found that locally and acutely increasing CREB levels in the dorsal hippocampus using viral vectors is sufficient to induce robust spatial memory in two conditions that do not normally support spatial memory, weakly trained wild-type (WT) mice and strongly trained mutant mice with a brain-wide disruption of CREB function. Together with previous results, these findings indicate that CREB is both necessary and sufficient for spatial memory formation, and highlight its pivotal role in the hippocampal molecular machinery underlying the formation of spatial memory.
Neurobiology of Learning and Memory
Frontiers in Neural Circuits
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
It has long been hypothesized that a primary function of the hippocampus is to discover and explo... more It has long been hypothesized that a primary function of the hippocampus is to discover and exploit temporal relationships between events. Previously, it has been reported that sequences of "time cells" in the hippocampus extend for tens of seconds. Other studies have shown that neuronal firing in the hippocampus fluctuates over hours and days. Both of these mechanisms could enable temporal encoding of events over very different timescales. However, thus far, these two classes of phenomena have never been observed simultaneously, which is necessary to ascribe broad-range temporal coding to the hippocampus. Using in vivo calcium imaging in unrestrained mice, we observed sequences of hippocampal neurons that bridged a 10 s delay. Similar sequences were observed over multiple days, but the set of neurons participating in those sequences changed gradually. Thus, the same population of neurons that encodes temporal information over seconds can also be used to distinguish periods of time over much longer timescales. These results unify two previously separate paradigms of temporal processing in the hippocampus that support episodic memory.
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature
Recent studies identified neuronal ensembles and circuits that hold specific memory information (... more Recent studies identified neuronal ensembles and circuits that hold specific memory information (memory engrams). Memory engrams are retained under protein synthesis inhibition-induced retrograde amnesia. These engram cells can be activated by optogenetic stimulation for full-fledged recall, but not by stimulation using natural recall cues (thus, amnesia). We call this state of engrams "silent engrams" and the cells bearing them "silent engram cells." The retention of memory information under amnesia suggests that the time-limited protein synthesis following learning is dispensable for memory storage, but may be necessary for effective memory retrieval processes. Here, we show that the fullfledged optogenetic recall persists at least 8 d after learning under protein synthesis inhibition-induced amnesia. This long-term retention of memory information correlates with equally persistent retention of functional engram cell-to-engram cell connectivity. Furthermore, inactivation of the connectivity of engram cell ensembles with its downstream counterparts, but not upstream ones, prevents optogenetic memory recall. Consistent with the previously reported lack of retention of augmented synaptic strength and reduced spine density in silent engram cells, optogenetic memory recall under amnesia is stimulation strength-dependent, with low-power stimulation eliciting only partial recall. Finally, the silent engram cells can be converted to active engram cells by overexpression of α-p-21-activated kinase 1, which increases spine density in engram cells. These results indicate that memory information is retained in a form of silent engram under protein synthesis inhibition-induced retrograde amnesia and support the hypothesis that memory is stored as the specific connectivity between engram cells. memory | engram | hippocampus | episodic | amnesia A memory engram is the enduring physical or chemical changes that occur in brain networks upon learning, representing the acquired memory information. Memory engrams are held by a set of neuronal ensembles that are activated by learning, and reactivation of these neurons gives rise to recall of the specific memory (1-3). A combination of immediate early genes, transgenics, and optogenetic techniques has recently provided the long-sought gain-of-function evidence for engram cells in the dentate gyrus of the hippocampus (4-6). This evidence has been complemented by loss-of-function evidence in the lateral amygdala (7, 8). Further studies identified and investigated memory engram cells in various brain areas under a variety of mnemonically relevant behavioral protocols (9-18). Furthermore, optogenetic manipulations of specific engram cells in vivo permitted unprecedented investigations of the relationship between memory representations and animal cognition or behaviors, allowing inception of a false memory (5), switching memory valence (19, 20), ameliorating depression-like behaviors (21), and restoring a memory impairment in early Alzheimer's mice (22). Another important benefit of engram cell identification is that it permits investigation of the fundamental synaptic, cellular, and circuit mechanisms for encoding, consolidation, and retrieval of
F1000 - Post-publication peer review of the biomedical literature
Memories become less precise and generalize over time as memory traces reorganize in hippocampal-... more Memories become less precise and generalize over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision characterizes overgeneralization of fear in post-traumatic stress disorder (PTSD) and age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by socalled "engram-bearing" dentate granule cells (eDGCs). Here we show using rodents that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (abLIM3) as a mossy fiber terminal localized cytoskeletal factor, whose levels decrease upon learning. Downregulation of abLIM3 in DGCs was sufficient to increase connectivity with CA3 stratum lucidum interneurons (SLINs), promote parvalbumin (PV) SLIN activation, enhance feed-forward Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
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Papers by Sheena Josselyn