scholarly journals Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

2019 ◽  
Author(s):  
David Levitan ◽  
Chenghao Liu ◽  
Tracy Yang ◽  
Yasuyuki Shima ◽  
Jian-You Lin ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Basolateral Amygdala ◽  
Molecular Mechanisms ◽  
Early Gene ◽  
Intrinsic Excitability ◽  
Long Term Memory ◽  
Projection Neurons ◽  
Term Memory ◽  
Growth Metabolism

AbstractConditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms are poorly understood, however. We used RNAseq from BLApn to identify learning-related changes in Stk11, a kinase with well-studied roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 restricted to BLApn completely blocks memory when occurring prior to training, but not following it, despite altering neither BLApn-dependent encoding of taste palatability in gustatory cortex, nor transcriptional activation of BLApn during training. Deletion of Stk11 in BLApn also increases their intrinsic excitability. Conversely, BLApn activated by CTA to express the immediate early gene Fos had reduced excitability. BLApn knockout of Fos also increased excitability and impaired learning. These data suggest that Stk11 and Fos expression play key roles in CTA long-term memory formation, perhaps by modulating the intrinsic excitability of BLApn.

scholarly journals Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
David Levitan ◽  
Chenghao Liu ◽  
Tracy Yang ◽  
Yasuyuki Shima ◽  
Jian-You Lin ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Molecular Mechanisms ◽  
Neuronal Excitability ◽  
Early Gene ◽  
Intrinsic Excitability ◽  
Long Term Memory ◽  
Projection Neurons ◽  
Impaired Memory ◽  
Kinase Pathway

Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms remain poorly understood. RNAseq from BLApn identified changes in multiple candidate learning-related transcripts including the expected immediate early gene Fos and Stk11, a master kinase of the AMP-related kinase pathway with important roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 in BLApn blocked memory prior to training, but not following it and increased neuronal excitability. Conversely, BLApn had reduced excitability following CTA. BLApn knockout of a second learning-related gene, Fos, also increased excitability and impaired learning. Independently increasing BLApn excitability chemogenetically during CTA also impaired memory. STK11 and C-FOS activation were independent of one another. These data suggest key roles for Stk11 and Fos in CTA long-term memory formation, dependent at least partly through convergent action on BLApn intrinsic excitability.

scholarly journals CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Xiao-Wen Yu ◽  
Daniel M Curlik ◽  
M Matthew Oh ◽  
Jerry CP Yin ◽  
John F Disterhoft
Keyword(s):  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Dorsal Hippocampus ◽  
Memory Deficits ◽  
Camp Response Element Binding ◽  
Intrinsic Excitability ◽  
Long Term Memory ◽  
Term Memory ◽  
Age Related

The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline.

scholarly journals ELAV proteins bind and stabilize C/EBP mRNA in the induction of long-term memory in Aplysia

2020 ◽  
Author(s):  
Anastasios A. Mirisis ◽  
Ashley M. Kopec ◽  
Thomas J. Carew
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Early Gene ◽  
Long Term Memory ◽  
Term Memory ◽  
New Findings

AbstractLong-term memory (LTM) formation is a critical survival process by which an animal retains information about prior experiences in order to guide future behavior. In the experimentally advantageous marine mollusk Aplysia, LTM for sensitization can be induced by the presentation of two aversive shocks to the animal’s tail. Each of these training trials recruits distinct growth factor signaling systems that promote LTM formation. Specifically, whereas intact TrkB signaling during Trial 1 promotes an initial and transient increase of the immediate early gene apc/ebp mRNA, a prolonged increase in apc/ebp gene expression required for LTM formation requires the addition of TGFβ signaling during Trial 2. Here we explored the molecular mechanisms by which Trial 2 achieves the essential prolonged gene expression of apc/ebp. We find that this prolonged gene expression is not dependent on de novo transcription, but that apc/ebp mRNA synthesized by Trial 1 is post-transcriptionally stabilized by interacting with the RNA-binding protein ApELAV. This interaction is promoted by p38 MAPK activation initiated by TGFβ. We further demonstrate that blocking the interaction of ApELAV with its target mRNA during Trial 2 blocks both the prolonged increase in apc/ebp gene expression and the behavioral induction of LTM. Collectively, our findings elucidate both when and how ELAV proteins are recruited for the stabilization of mRNA in LTM formation.Significance StatementIn the present paper we significantly extend the general field of molecular processing in LTM by describing a novel form of pre-translational processing required for LTM which relies on the stabilization of a newly synthesized mRNA by a unique class of RNA binding proteins (ELAVs). In the broad field of molecular mechanisms of transcription-dependent LTM, there are now compelling data showing that important processing can occur after transcription of a gene, but before translation of the message into protein. Although the potential importance of ELAV proteins in LTM formation has previously been reported, to date there has been no mechanistic insight into the specific actions of ELAV proteins in stabilization of mRNAs known to be critical for LTM. Our new findings thus complement and extend this literature by demonstrating when and how this post-transcriptional gene regulation is mediated in the induction of LTM.

scholarly journals Temporally-precise basolateral amygdala activation is required for the formation of taste memories in gustatory cortex

2020 ◽  
Author(s):  
Elor Arieli ◽  
Ron Gerbi ◽  
Mark Shein-Idelson ◽  
Anan Moran
Keyword(s):  
Basolateral Amygdala ◽  
Time Lag ◽  
Nucleus Basalis ◽  
Electrophysiological Recording ◽  
Long Term Memory ◽  
Projection Neurons ◽  
Dynamic Activity ◽  
Gustatory Cortex ◽  
Taste Experience

AbstractLearning to associate malaise with the intake of novel food is critical for survival. Since food poisoning may take hours to affect, animals developed brain circuits to transform the current novel taste experience into a taste memory trace (TMT) and bridge this time lag. Ample studies showed that the basolateral amygdala (BLA), the nucleus basalis magnocellularis (NBM) and the gustatory cortex (GC) are involved in TMT formation and taste-malaise association. However, how dynamic activity across these brain regions during novel taste experience promotes the formation of these memories is currently unknown. We used the conditioned taste aversion (CTA) learning paradigm in combination with short-term optogenetics and electrophysiological recording in rats to test the hypothesis that temporally specific activation of BLA projection neurons is essential for TMT formation in the GC, and consequently CTA. We found that late-epoch (LE, >800ms), but not the early epoch (EE, 200-700ms), BLA activation during novel taste experience is essential for normal CTA, for early c-Fos expression in the GC (a marker of TMT formation) and for the subsequent changes in GC ensemble palatability coding. Interestingly, BLA activity was not required for intact taste identity or palatability perceptions. We further show that BLA-LE information is transmitted to GC through the BLA→NBM pathway where it affects the formation of taste memories. These results expose the dependence of long-term memory formation on specific temporal windows during sensory responses and the distributed circuits supporting this dependence.SignificanceConsumption of a novel taste may result in malaise and poses a threat to animals. Since the effects of poisoning appear only hours after consumption, animals must store the novel taste’s information in memory until they associate it with its value (nutritious or poisonous). Here we elucidate the neuronal activity patterns and circuits that support the processing and creation of novel-taste memories in rats. Our results show that specific patterns of temporal activation in the basolateral amygdala transmitted across brain areas are important for formation of taste memory and taste-malaise association. These findings may shed light on long-term activity-to-memory transformation in other sensory modalities.

scholarly journals Preferred hexoses influence long-term memory and induction of lactose catabolism byStreptococcus mutans

2018 ◽  
Author(s):  
Lin Zeng ◽  
Robert A. Burne
Keyword(s):  
Dental Caries ◽  
Molecular Mechanisms ◽  
Sugar Metabolism ◽  
Prior Exposure ◽  
Lag Phase ◽  
Long Term Memory ◽  
Term Memory ◽  
Free Glucose ◽  
Lactose Utilization

ABSTRACTBacteria prioritize sugar metabolism via carbohydrate catabolite repression, which regulates global gene expression to optimize the catabolism of preferred substrates. Here, we report an unusual long-term memory effect in certainStreptococcus mutansstrains that alters adaptation to growth on lactose after prior exposure to glucose or fructose. In strain GS-5, cells that were first cultured on fructose then transferred to lactose displayed an exceptionally long lag (>11 h) and slower growth, compared to cells first cultured on glucose or cellobiose, which displayed a reduction in lag phase by as much as 10 h. Mutants lacking the cellobiose-PTS or phospho-β-glucosidase lost the accelerated growth on lactose associated with prior culturing on glucose. The memory effects of glucose or fructose on lactose catabolism were not as profound in strain UA159, but the lag phase was considerably shorter in mutants lacking the glucose-PTS EIIMan. Interestingly, whenS.mutanswas cultivated on lactose, significant quantities of free glucose accumulated in the medium, with higher levels found in the cultures of strains lacking EIIMan, glucokinase, or both. Free glucose was also detected in cultures that were utilizing cellobiose or trehalose, albeit at lower levels. Such release of hexoses byS.mutansis likely of biological significance as it was found that cells required small amounts of glucose or other preferred carbohydrates to initiate efficient growth on lactose. These findings suggest thatS.mutansmodulates the induction of lactose utilization based on its prior exposure to glucose or fructose, which can be liberated from common disaccharides.IMPORTANCEUnderstanding the molecular mechanisms employed by oral bacteria to control sugar metabolism is key to developing novel therapies for management of dental caries and other oral diseases. Lactose is a naturally occurring disaccharide that is abundant in dairy products and commonly ingested by humans. However, for the dental caries pathogenStreptococcus mutans, relatively little is known about the molecular mechanisms that regulate expression of genes required for lactose uptake and catabolism. Two peculiarities of lactose utilization byS.mutansare explored here: a)S.mutansexcretes glucose that it cleaves from lactose and b) prior exposure to certain carbohydrates can result in a long-term inability to use lactose. The study begins to shed light on howS.mutansmay bet-hedge to optimize its persistence and virulence in the human oral cavity.

scholarly journals Long-Term Memory for Pavlovian Fear Conditioning Requires Dopamine in the Nucleus Accumbens and Basolateral Amygdala

PLoS ONE ◽  
2010 ◽  
Vol 5 (9) ◽  
pp. e12751 ◽  
Author(s):  
Jonathan P. Fadok ◽  
Martin Darvas ◽  
Tavis M. K. Dickerson ◽  
Richard D. Palmiter
Keyword(s):  
Nucleus Accumbens ◽  
Fear Conditioning ◽  
Basolateral Amygdala ◽  
Long Term Memory ◽  
Pavlovian Fear Conditioning ◽  
Term Memory
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