Search PubMed⌕ Search

Biomedical subjects

Sheena A Josselyn

Publications and source records attributed to Sheena A Josselyn.

9 recordsLinked to original sources
PubMed2026

Disruption of major Ptchd1 isoforms causes autistic traits in social behavior and communication.

PTCHD1 is an X-linked three-exon gene associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). Mice lacking Ptchd1 exon 2 (Ptchd1Δexon2) exhibit hyperactivity and learning impairments, but do not recapitulate ASD-like traits. Through mapping of clinically reported loss-of-function mutations in human patients, we determined that PTCHD1 exon 3 is a high-risk locus. We therefore generated an alternative Ptchd1 knockout mouse model by targeting Ptchd1 exon 3 (Ptchd1Δexon3) using CRISPR/Cas9. Our analyses revealed that two major PTCHD1/Ptchd1 transcripts-a (full-length) and c (shorter)-were expressed in the brain. In Ptchd1Δexon2 mice, Ptchd1_a was lost, but Ptchd1_c was compensatorily upregulated, and these mice showed no ASD-like social deficits. In Ptchd1Δexon3 mutants, both Ptchd1_a and Ptchd1_c were lost, along with dysregulation of social and communication behaviors, increased repetitive behavior, and motor and learning impairments. Our side-by-side analyses of Ptchd1Δexon2 and Ptchd1Δexon3 mice suggest a functional link between PTCHD1/Ptchd1 and ASD, demonstrating that loss-of-function mutations disrupting C-terminal Ptchd1 lead to robust ASD-relevant phenotypes in mice, more faithfully recapitulating clinically observed traits.

Animals↗
PubMed2005

The nucleus accumbens is not critically involved in mediating the effects of a safety signal on behavior.

Although considerable progress has been made towards understanding the neural systems mediating conditioned fear, little is known about the neural mechanisms underlying conditioned inhibitors of fear (or safety signals). The present series of experiments examined the involvement of the nucleus accumbens (NAC) in mediating the effects of safety signals on behavior using a conditioned inhibition of fear-potentiated startle paradigm. Neither increasing dopaminergic nor decreasing glutamatergic function in the NAC altered the magnitude of conditioned fear or conditioned inhibition of fear in rats. Furthermore, large pre- or post-training electrolytic lesions of the NAC did not affect acquisition or expression of fear-potentiated startle or conditioned inhibition of fear-potentiated startle. Taken together, these data suggest that the NAC is not critically involved in the acquisition or expression of fear-potentiated startle or conditioned inhibition of fear-potentiated startle. Previous research has implicated the NAC in 'reward-attenuated startle' in which presentation of a stimulus paired with food decreased startle responding. The present results, therefore, indicate important neural dissociations between the processing of appetitive and safety signals, even though behavioral studies and learning theories have suggested that these two forms of learning share some commonalities.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2005

CREB, synapses and memory disorders: past progress and future challenges.

In neurons, appropriate long-term adaptive responses to changes in the environment require the conversion of extracellular stimuli into discrete intracellular signals. Many of these signals involve the regulation of gene expression. The cAMP responsive element binding protein (CREB) is a nuclear transcription factor that modulates transcription of genes containing cAMP responsive elements (CRE sites) in their promoters. CREB is a key part of many intracellular signaling events that critically regulate many neural functions. Numerous studies on invertebrates and vertebrates demonstrate that CREB is critical for long-term memory. Here, we review the key features of CREB-dependent transcription and critically evaluate the data examining the roles of CREB in different forms of plasticity, including long-term memory in mammals. Because learning and memory have been linked to specific types of synaptic plasticity in several species, we also review studies on the role of CREB in long-term facilitation in Aplysia and in hippocampal long-term potentiation (LTP). Several human cognitive disorders have been linked to alterations of CREB-regulated gene expression. Therefore, we explore the possibility of targeting CREB function in developing novel treatment strategies. Finally, we highlight areas of research on CREB that are ripe for further advancement.

Animals↗
PubMed2004

Memory reconsolidation and extinction have distinct temporal and biochemical signatures.

Memory retrieval is not a passive phenomenon. Instead, it triggers a number of processes that either reinforce or alter stored information. Retrieval is thought to activate a second memory consolidation cascade (reconsolidation) that requires protein synthesis. Here, we show that the temporal dynamics of memory reconsolidation are dependent on the strength and age of the memory, such that younger and weaker memories are more easily reconsolidated than older and stronger memories. We also report that reconsolidation and extinction, two opposing processes triggered by memory retrieval, have distinct biochemical signatures: pharmacological antagonism of either cannabinoid receptor 1 or L-type voltage-gated calcium channels blocks extinction but not reconsolidation. These studies demonstrate the dynamic nature of memory processing after retrieval and represent a first step toward a molecular dissection of underlying mechanisms.

Animals↗
PubMed2004

Consolidation of CS and US representations in associative fear conditioning.

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 one-trial 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.

Animals↗
PubMed2003

MAPK, CREB and zif268 are all required for the consolidation of recognition memory.

There has been nearly a century of interest in the idea that encoding and storage of information in the brain requires changes in the efficacy of synaptic connections between neurons that are activated during learning. Recent research into the molecular mechanisms of long-term potentiation (LTP) has brought about new knowledge that has provided valuable insights into the neural mechanisms of memory storage. The evidence indicates that rapid activation of the genetic machinery can be a key mechanism underlying the enduring modification of neural networks required for the stability of memories. In recent years, a wealth of experimental data has highlighted the importance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling in the regulation of gene transcription in neurons. Here, we briefly review experiments that have shown MAPK/ERK, cAMP response element-binding protein (CREB) and the immediate early gene (IEG) zif268 are essential components of a signalling cascade required for the expression of late phase LTP and of certain forms of long-term memory. We also present experiments in which we have assessed the role of these three molecules in recognition memory. We show that pharmacological blockade of MAPK/ERK phosphorylation, functional inactivation of CREB in an inducible transgenic mouse and inactivation of zif268 in a mutant mouse result in a similar deficit in long-term recognition memory. In the continuing debate about the role of LTP mechanisms in memory, these findings provide an important complement to the suggestion that synaptic changes brought about by LTP and memory consolidation and storage share, at least in part, common underlying molecular mechanisms.

Animals↗
PubMed2002

CREB required for the stability of new and reactivated fear memories.

The cAMP-responsive element binding protein (CREB) family of transcription factors is thought to be critical in memory formation. To define the role of CREB in distinct memory processes, we derived transgenic mice with an inducible and reversible CREB repressor by fusing CREBS133A to a tamoxifen (TAM)-dependent mutant of an estrogen receptor ligand-binding domain (LBD). We found that CREB is crucial for the consolidation of long-term conditioned fear memories, but not for encoding, storage or retrieval of these memories. Our studies also showed that CREB is required for the stability of reactivated or retrieved conditioned fear memories. Although the transcriptional processes necessary for the stability of initial and reactivated memories differ, CREB is required for both. The findings presented here delineate the memory processes that require CREB and demonstrate the power of LBD-inducible transgenic systems in the study of complex cognitive processes.

Animals↗