The ability to learn new information and behaviors is a vital component of survival in most animal species. This learning can occur via direct experience or through observation of another individual (i.e., social learning). While research focused on understanding the neural mechanisms of direct learning is prevalent, less work has aimed at understanding the brain circuitry mediating the acquisition and recall of socially acquired information. We aimed to further elucidate the mechanisms underlying recall of socially acquired information by having rats sequentially recall a socially transmitted food preference (STFP) and a fear association via fear conditioning by-proxy (FCbP). Brain tissue was processed for mRNA expression of the immediate early gene (IEG) Arc, which reliably expresses in the cell nucleus following transcription before migrating to the cytoplasm over the next 25 minutes. Given this timeframe, we were able to identify whether Arc transcription was triggered by STFP recall, FCbP recall, or following recall of both memories. Surprisingly – and contrary to past research examining expression of other IEGs following STFP or FCbP recall separately – we found no differences in any of the Arc expression measures across a number of prefrontal regions and the vCA3 of the hippocampus between controls, demonstrators, and observers, though we did detect an overall effect of sex in a number of regions. We theorize that these results may indicate that relatively little Arc-dependent neural restructuring is taking place in the prefrontal cortices following recall of a recently socially acquired information or directly acquired fear associations in these areas.
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Infusion of etoposide in the CA1 disrupts hippocampal immediate early gene expression and hippocampus-dependent learning
Tight regulation of immediate early gene (IEG) expression is important for synaptic plasticity, learning, and memory. Recent work has suggested that DNA double strand breaks (DSBs) may have an adaptive role in post-mitotic cells to induce IEG expression. Physiological activity in cultured neurons as well as behavioral training leads to increased DSBs and subsequent IEG expression. Additionally, infusion of etoposide—a common cancer treatment that induces DSBs—impairs trace fear memory. Here, we assessed the effects of hippocampal infusion of 60 ng of etoposide on IEG expression, learning, and memory in 3–4 month-old C57Bl/6J mice. Etoposide altered expression of the immediate early genes
- NSF-PAR ID:
- 10375517
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 12
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Learning can occur via direct experience or through observation of another individual (i.e., social learning). While research focused on understanding the neural mechanisms of direct learning is prevalent, less work has examined the brain circuitry mediating the acquisition and recall of socially acquired information. Here, we aimed to further elucidate the mechanisms underlying recall of socially acquired information by having male and female rats sequentially recall a socially transmitted food preference (STFP) and a fear association via fear conditioning by-proxy (FCbP). Brain tissue was processed for mRNA expression of the immediate early gene (IEG) Arc , which expresses in the nucleus following transcription before migrating to the cytoplasm over the next 25 min. Given this timeframe, we could identify whether Arc transcription was triggered by STFP recall, FCbP recall, or both. Contrary to past research, we found no differences in any Arc expression measures across a number of prefrontal regions and the ventral CA3 of the hippocampus between controls, demonstrators, and observers. We theorize that these results may indicate that relatively little Arc- dependent neural restructuring is taking place in the prefrontal cortices and ventral CA3 following recall of recently socially acquired information or directly acquired fear associations in these areas.more » « less
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Neuronal Kv7/Potassium Voltage-Gated Channel Subfamily Q (KCNQ) potassium channels underlie M-current that potently suppresses repetitive and burst firing of action potentials (APs). They are mostly heterotetramers of Kv7.2 and Kv7.3 subunits in the hippocampus and cortex, the brain regions important for cognition and behavior. Underscoring their critical roles in inhibiting neuronal excitability, autosomal dominantly inherited mutations in Potassium Voltage-Gated Channel Subfamily Q Member 2 (
KCNQ2 ) and Potassium Voltage-Gated Channel Subfamily Q Member 3 (KCNQ3 ) genes are associated with benign familial neonatal epilepsy (BFNE) in which most seizures spontaneously remit within months without cognitive deficits.De novo mutations inKCNQ2 also cause epileptic encephalopathy (EE), which is characterized by persistent seizures that are often drug refractory, neurodevelopmental delay, and intellectual disability. Heterozygous expression of EE variants ofKCNQ2 is recently shown to induce spontaneous seizures and cognitive deficit in mice, although it is unclear whether this cognitive deficit is caused directly by Kv7 disruption or by persistent seizures in the developing brain as a consequence of Kv7 disruption. In this study, we examined the role of Kv7 channels in learning and memory by behavioral phenotyping of theKCNQ 2+/−mice, which lack a single copy ofKCNQ2 but dos not display spontaneous seizures. We found that bothKCNQ 2+/−and wild-type (WT) mice showed comparable nociception in the tail-flick assay and fear-induced learning and memory during a passive inhibitory avoidance (IA) test and contextual fear conditioning (CFC). Both genotypes displayed similar object location and recognition memory. These findings together provide evidence that heterozygous loss ofKCNQ2 has minimal effects on learning or memory in mice in the absence of spontaneous seizures. -
Immediate-early gene (IEG) expression has been used to identify small neural ensembles linked to a particular experience, based on the principle that a selective subset of activated neurons will encode specific memories or behavioral responses. The majority of these studies have focused on “engrams” in higher-order brain areas where more abstract or convergent sensory information is represented, such as the hippocampus, prefrontal cortex, or amygdala. In primary sensory cortex, IEG expression can label neurons that are responsive to specific sensory stimuli, but experience-dependent shaping of neural ensembles marked by IEG expression has not been demonstrated. Here, we use a fosGFP transgenic mouse to longitudinally monitor in vivo expression of the activity-dependent gene c-fos in superficial layers (L2/3) of primary somatosensory cortex (S1) during a whisker-dependent learning task. We find that sensory association training does not detectably alter fosGFP expression in L2/3 neurons. Although training broadly enhances thalamocortical synaptic strength in pyramidal neurons, we find that synapses onto fosGFP+ neurons are not selectively increased by training; rather, synaptic strengthening is concentrated in fosGFP− neurons. Taken together, these data indicate that expression of the IEG reporter fosGFP does not facilitate identification of a learning-specific engram in L2/3 in barrel cortex during whisker-dependent sensory association learning.more » « less
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Summary Objective Seizures develop in 80% of patients with anti–
N ‐methyl‐d ‐aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti‐NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti‐NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures.Methods We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti‐NMDAR encephalitis or polyclonal rabbit anti‐NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2‐week treatment was assessed with video‐electroencephalography. We assessed memory, anxiety‐related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole‐cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures.
Results Prolonged exposure to rabbit anti‐NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety‐related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice.
Significance Our findings indicate that autoantibodies can induce seizures in anti‐NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.
