A New Cell Type in the Hippocampus Contributes to Sharp Waves Involved in Memory

What's the science?

The dentate gyrus and the CA3 are two important regions involved in memory in the hippocampus. The dentate gyrus separates out incoming signals from the cortex and relays patterns of information to the CA3 pyramidal cells via thorny “mossy fiber” projections. Cues can then reactivate this pattern of information in the CA3 cells (also known as pattern completion). The way in which CA3 neurons are able to reactivate the neurons encoding a memory involves recurrent network activity, however the details are not well understood. Understanding differences in cell types within the CA3 of the hippocampus could improve our understanding of this process of reactivating memories. This week in Nature Neuroscience, Hunt and colleagues examine different pyramidal cell types within the CA3 and their activity patterns during sharp waves (i.e. spontaneous reactivation of memory neurons) to understand their role in the “replay” of memory.

How did they do it?

They performed whole-cell patch-clamp on hippocampal tissue slices from mice to assess how the neurons in the CA3 would fire in response to current injection (to cause action potential firing). They then examined the structural and molecular properties of these neurons to see how cell types within the CA3 differed. Next, they used a transgenic mouse line and optogenetics to express light activated channels in mossy fiber axons projecting to CA3 cells from the dentate gyrus. They activated these fibers and measured excitatory post-synaptic currents to map input from dentate gyrus to different pyramidal cells within the CA3. In mice, they measured activity (local field potentials and multi-unit activity) of different labelled pyramidal cells during “sharp wave” events, which are the spontaneous neuron firing events in the CA3, known to be important for memory. The goal was to understand how different pyramidal cells and their firing properties contribute to memory. They used optogenetic activation of cholinergic neurons, which are known to regulate memory in the hippocampus, to test how different pyramidal cell types responded to cholinergic modulation. Lastly, they constructed an “attractor network model” to show how these different cell types contribute to network dynamics in the hippocampus during memory replay.

What did they find?

There were two types of responses from neurons within the CA3 after current injection: neurons that fired in a regular pattern and neurons that fired in a “burst” pattern. The regular firing neurons had thorny spines as expected of CA3 cells, however the burst firing neurons did not have thorny spines (i.e athorny cells). Using a clustering approach, the two cell types were segregated based on their different electrophysiological and structural properties. Using optogenetic activation of mossy fibers, they found that mossy fibers project to regular thorny neurons but not to athorny burst firing neurons in the CA3. However, both thorny and athorny neurons were excited by recurrent activation (i.e. by neurons nearby).

In mice, they measured neuron activity during sharp wave events, which had two phases: an initial ramp phase followed by an exponential increase in firing. They measured properties of firing of the two cell types and found that they behaved differently: thorny cells contribute to initial single spike activity and this spiking peaked during the exponential phase of the sharp wave event, while athorny cells weakly increased their single spike rate during the ramp and exponential phase of the sharp wave event. Athorny neurons contributed more to the complex burst firing (as opposed to single unit firing) component of sharp wave events. Optogenetic activation of cholinergic cells abolished sharp wave events, indicating that sharp waves are regulated by acetylcholine (a neurotransmitter that modulates activity). Further, activation of cholinergic neurons downregulated the burst firing of the athorny pyramidal cells, suggesting that low acetylcholine levels may facilitate the reactivation of pyramidal cells during the “replay” of memory during sharp wave events. Using an “attractor network model” they found that burst firing (driven by athorny cells) were important for evoking sharp wave events, suggesting that these newly defined cells are crucial for memory replay.

What's the impact?

This is the first study to demonstrate that a new “athorny” cell type in the CA3 region of the hippocampus is involved in memory. This new athorny neuron plays a role in burst firing associated with “sharp wave” events that are important for the reactivation of memory (i.e. memory replay). Understanding the cell types involved in memory circuits in the hippocampus is crucial to understanding how memory is encoded and retrieved.

Hunt et al., A novel pyramidal cell type promotes sharp-wave synchronization in the hippocampus. Nature Neuroscience (2018). Access the original scientific publication here.

Dialectical Behaviour Therapy is Effective For Adolescents at Risk of Suicide

What's the science?

Suicide rates among adolescents have increased in recent years, but no well-established treatment exists to decrease death by suicide in at-risk youth. Dialectical behavioural therapy (DBT) involves cognitive-behavioural treatment focused on reducing self-harm, skills for managing distress and emotion regulation. It was recently demonstrated to be effective in reducing self-harm and suicidal ideation in adolescents, however, it is critical to understand the effects of DBT on suicide attempts. This week in JAMA Psychiatry, McCauley and colleagues report on a randomized clinical trial comparing the effects of DBT with individual and group supportive therapy (IGST), which acts as a control that matches DBT on nonspecific treatment factors closely. 

How did they do it?

173 adolescents across multiple sites participated (aged 12-18). Participants had previously attempted suicide one or more times, had high levels of suicide ideation within the past year (Suicide Ideation Questionnaire Junior), had self-injured recently, and had 3 or more criteria for Borderline Personality Disorder. Participants were randomized to the DBT or IGST group, and both treatments involved 6 months of weekly individual and group therapies as well as parental participation. IGST treatment included group therapy, weekly consultation with a therapist, and emphasized belonging and connectedness. DBT treatment included skills training, group training with multiple families, and validation of interaction between families and adolescents. DBT treatment is similar to standard cognitive behavioural therapy but focuses on helping adolescents to ‘build a life worth living’ and on commitment to change. Suicide attempts and self harm were measured using the Suicide Attempt Self-Injury Interview (SASII), and suicidal ideation was measured using the Suicide Ideation Questionnaire Junior (SIQ-JR). A mixed model repeated measures analysis was used to compare treatment groups at four timepoints (baseline, 3, 6 (end of therapy), 9, and 12 months)

What did they find?

Between 0 (baseline) and 6 months of treatment, 10% of the DBT group and 22% of the IGST group attempted suicide. Between 6-12 months (a six month follow-up period), the rates were 7% of the DBT group and 10% of the IGST group. To analyze the number of suicide attempts and non-suicidal self injuries, a generalized linear mixed-effects model was used, and each participant was given a severity score. DBT improved each outcome measure. When the authors assessed the ‘number needed to treat’ they found that for each 8.46 youth who completed DBT instead of IGST, one additional youth would be free of suicide attempts (a small-medium effect size). Overall, the effects of DBT on primary outcomes were significant at 6 months but not at 12 months (after 6 months of follow-up). In a secondary analysis, self harm was classified in a binary manner instead of on a severity scale. A significantly larger proportion (46%) of youth who underwent DBT did not self harm by 6 months, compared to only 28% for IGST. By 12 months, the rates were 51% for the DBT group and 32% for the IGST group. There was also a large effect of DBT on reducing suicide ideation at 6 months (versus IGST), and a smaller effect at 12 months.

What's the impact?

This is the first study to demonstrate the effectiveness of DBT on reducing suicide attempts in youth. As there was less evidence for the effectiveness of DBT compared to the control treatment (IGST) at 12 months (versus immediately following treatment cessation at 6 months), long-term treatment may be recommended. Intensive family involvement and active coping skills (hallmarks of DBT) may be beneficial for youths at risk of self harm and suicide.

McCauley et al., Efficacy of Dialectical Behavior Therapy for Adolescents at High Risk for Suicide. JAMA Psychiatry (2018). Access the original scientific publication here.

A Role for Human Herpesvirus in Alzheimer’s disease

What's the science?

Alzheimer’s disease has previously been associated with various bacteria and viruses — in particular herpes simplex virus. However, the mechanism by which viruses may contribute to Alzheimer’s disease is not clear. This week in Neuron, Readhead and colleagues used a neuropathological network model (at the gene, transcription, protein, and histopathology levels) to understand the contribution of viruses to Alzheimer’s. 

How did they do it?

The authors obtained data from brains (after death) of healthy individuals, those with ‘pre-clinical’ Alzheimer’s (i.e. early, visible pathology but no cognitive impairment at time of death), and those with later stage Alzheimer’s disease. They first used computational modelling (they created probabilistic causal networks) to understand the differences in gene expression networks between healthy individuals and those with pre-clinical Alzheimer’s disease. They focused analyses on the entorhinal cortex and hippocampus (two regions affected by the disease). From the pre-clinical and control groups, they found genes they referred to as ‘network drivers’ that regulated a large portion of the gene expression in the network.

They then evaluated viral activity (viral RNA and DNA sequences) in patients with clinical Alzheimer’s (four independent cohorts) versus healthy controls. They first performed RNA sequencing in tissue from the superior temporal gyrus, anterior prefrontal cortex, inferior frontal gyrus, and parahippocampal gyrus obtained from one of the four cohorts, and looked for the presence of genes associated with viruses known to infect the human transcriptome. They also performed whole-exome sequencing to assess viral DNA in the same regions. The relationship between Alzheimer’s traits (Clinical Dementia Rating, Amyloid Plaque Density) and elevated viral RNA and DNA levels was also examined.

What did they find?

When the authors assessed pre-clinical Alzheimer’s versus healthy control gene networks, they found that promoters (i.e. the region of the gene that turns on transcription) for gene network drivers lost or gained in pre-clinical Alzheimer’s were enriched for C2H2 zinc factor transcription factor binding motifs. The “lost in pre-clinical Alzheimer’s disease” drivers had more G-quadruplex motifs within their genes. There was also a negative relationship between the density of G-quadruplex (co-regulatory with C2H2 transcription factor) and the expression of these genes in the entorhinal cortex in the pre-clinical Alzheimer’s and Alzheimer’s disease samples. These types of changes have been previously associated with viral biology/viral infection, suggesting that viral activity is associated with Alzheimer’s. As a second line of evidence, they found overlap between identified gene network drivers and gene targets of human microRNAs that had been previously associated with innate immunity and DNA viral activity.

When the authors assessed viral abundance in the brains of patients with Alzheimer’s, they found increased viral species in the anterior prefrontal cortex and superior temporal gyrus; in particular, HHV-7 and HHV-6A (i.e. herpesviruses). These elevated levels were also found in other brain regions in two additional cohorts of patients, suggesting that these viruses are increased across different tissues. The same findings were not present in samples of pathological aging or progressive supranuclear palsy (another neurodegenerative disorder), suggesting they are specific to Alzheimer’s. Increased viral DNA for HHV-6A was also detected. An HHV-7 gene and HHV-6A region were associated with Alzheimer’s traits (dementia ratings & plaque density) and viral abundance mediated gene expression of genes involved in disease risk and beta-amyloid processing (which form plaques). They also identified that some host genes (in particular the MIR155 host gene) regulated by HHV-6A (a herpesvirus) could form a network associated with neuronal loss, indicating that HHV-6A may be implicated in neurodegeneration. Finally, the authors performed some follow-up analyses in mice and found that MIR155 knockout mice had larger cortical amyloid plaques. Upregulated genes in MIR155 knockout mice were similar to those upregulated by the HHV-6A virus, suggesting that HHV-6A could act by inhibiting MIR155.

What's the impact?

This study provides genetic, clinical, and neuropathological evidence that there may be viral and host factors that interact to contribute to Alzheimer’s pathology. Viruses could potentially disturb biological processes (e.g. leading to plaque formation) or alter transcription or regulatory mechanisms. The contribution of viral activity in Alzheimer’s should be further investigated.

Readhead et al., Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron (2018). Access the original scientific publication here.