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 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 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 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 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 Molecular Mechanisms of Oxytocin Signaling at the Synaptic Connection

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Jan Bakos ◽  
Annamaria Srancikova ◽  
Tomas Havranek ◽  
Zuzana Bacova
Keyword(s):  
Neurodevelopmental Disorders ◽  
Molecular Mechanisms ◽  
Neuronal Excitability ◽  
Molecular Level ◽  
Short Term ◽  
Oxytocin Receptors ◽  
Potential Therapeutic Intervention ◽  
Early Alteration

Aberrant regulation of oxytocin signaling is associated with the etiology of neurodevelopmental disorders. Synaptic dysfunctions in neurodevelopmental disorders are becoming increasingly known, and their pathogenic mechanisms could be a target of potential therapeutic intervention. Therefore, it is important to pay attention to the role of oxytocin and its receptor in synapse structure, function, and neuron connectivity. An early alteration in oxytocin signaling may disturb neuronal maturation and may have short-term and long-term pathological consequences. At the molecular level, neurodevelopmental disorders include alterations in cytoskeletal rearrangement and neuritogenesis resulting in a diversity of synaptopathies. The presence of oxytocin receptors in the presynaptic and postsynaptic membranes and the direct effects of oxytocin on neuronal excitability by regulating the activity of ion channels in the cell membrane implicate that alterations in oxytocin signaling could be involved in synaptopathies. The ability of oxytocin to modulate neurogenesis, synaptic plasticity, and certain parameters of cytoskeletal arrangement is discussed in the present review.

scholarly journals Chronic Fluoxetine Treatment Induces Brain Region-Specific Upregulation of Genes Associated with BDNF-Induced Long-Term Potentiation

2007 ◽  
Vol 2007 ◽  
pp. 1-9 ◽  
Author(s):  
Maria Nordheim Alme ◽  
Karin Wibrand ◽  
Grethe Dagestad ◽  
Clive R. Bramham
Keyword(s):  
Dentate Gyrus ◽  
Brain Region ◽  
Molecular Mechanisms ◽  
Antidepressant Treatment ◽  
Antidepressant Drugs ◽  
Long Term Potentiation ◽  
Specific Pattern ◽  
Early Gene ◽  
Term Potentiation

Several lines of evidence implicate BDNF in the pathogenesis of stress-induced depression and the delayed efficacy of antidepressant drugs. Antidepressant-induced upregulation of BDNF signaling is thought to promote adaptive neuronal plasticity through effects on gene expression, but the effector genes downstream of BDNF has not been identified. Local infusion of BDNF into the dentate gyrus induces a long-term potentiation (BDNF-LTP) of synaptic transmission that requires upregulation of the immediate early gene Arc. Recently, we identified five genes (neuritin, Narp, TIEG1, Carp, and Arl4d) that are coupregulated with Arc during BDNF-LTP. Here, we examined the expression of these genes in the dentate gyrus, hippocampus proper, and prefrontal cortex after antidepressant treatment. We show that chronic, but not acute, fluoxetine administration leads to upregulation of these BDNF-LTP-associated genes in a brain region-specific pattern. These findings link chronic effects of antidepressant treatment to molecular mechanisms underlying BDNF-induced synaptic plasticity.

scholarly journals A Unique Mouse Model of Early Life Exercise Enables Hippocampal Memory and Synaptic Plasticity

2019 ◽  
Author(s):  
Autumn S. Ivy ◽  
Tim Yu ◽  
Enikö Kramár ◽  
Sonia Parievsky ◽  
Fred Sohn ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Early Life ◽  
Molecular Mechanisms ◽  
Memory Task ◽  
Long Term Potentiation ◽  
Long Term Memory ◽  
Critical Periods ◽  
Juvenile Period ◽  
Cognitive Benefits

AbstractAerobic exercise is a powerful modulator of learning and memory. Molecular mechanisms underlying the cognitive benefits of exercise are well documented in adult rodents. Animal models of exercise targeting specific postnatal periods of hippocampal development and plasticity are lacking. Here we characterize a model of early-life exercise (ELE) in male and female mice designed with the goal of identifying critical periods by which exercise may have a lasting impact on hippocampal memory and synaptic plasticity. Mice freely accessed a running wheel during three postnatal periods: the 4th postnatal week (juvenile ELE, P21-27), 6th postnatal week (adolescent ELE, P35-41), or 4th-6th postnatal weeks (juvenile-adolescent ELE, P21-41). All exercise groups significantly increased their running distances over time. When exposed to a weak learning stimulus, mice that had exercised during the juvenile period were able to form lasting long-term memory for a hippocampus-dependent spatial memory task. Electrophysiological experiments revealed enhanced long-term potentiation in hippocampal CA1 the juvenile-adolescent ELE group only. Furthermore, basal synaptic transmission was significantly increased in all mice that exercised during the juvenile period. Our results suggest early-life exercise can enable hippocampal memory, synaptic plasticity, and basal synaptic physiology when occurring during postnatal periods of hippocampal maturation.

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