2019 Biopsych Seminar Thursdays

This week we take a look at two articles form early 2006 focused on animal models of schizophrenia. Each of the articles develops and tests a distinct mouse model for schizophrenia. Importantly, both of these models are especially focused on the cognitive symptoms of schizophrenia, which other models do not present and which are not primarily targeted by current treatment in humans.  In the article by Moore and colleagues (2006), the model is achieved by disrupting embryonic development of paralimbic frontal and temporal cortices, while in the article by Kellendonk and colleagues (2006) the model is achieved by overexpressing D2 receptors in the striatum. Results in cognitive tasks are not unlike in the two models, which highlights the fact the schizophrenia might be better conceptualized as a heterogeneous disease in which different neurobiological substrates given origin to similar symptoms across individuals. This means that not one model might be truer to the human disord...

Moore et al and Kellendonk et al investigated the neural effects of altering two distinct hypotheses for the origin of schizophrenia symptoms in humans: increased amounts of the dopamine signaling in the striatum compared to asymptomatic conditions and gray matter reductions throughout the cortex and thalamus without affecting the actual neuronal cell count. These groups produced differential results based on whether they reversibly overexpressed D2Rs in the striatum via a transgenic mouse line (Kellendonk) or used MAM, a methylating agent, to stunt embryonic brain development via administration to the pregnant dam at either the litter’s embryonic day 15 or 17 (Moore). Both groups’ measures of assessing schizophrenic symptoms in mice were quite interesting, I found, as I could not previously imagine how a research group might go about quantifying schizophrenia without being able to listen to the thought patterns of the mice. Methods included open field testing to assess o...

            The papers this week both focused on animal models of schizophrenia, a rather uniquely challenging mental illness. Kellendork  et al.  investigated the link between overactive dopamine function and schizophrenia-like behaviors and changes in mice. Moore  et al.  took an extremely different approach by specifically targeting specific cortical development in rat embryos. Despite both papers’ similarity and the fact that they were published the same year, they have very different styles. I assume this was due to some combination of different journal expectations and differing backgrounds of the authors, but it was interesting to notice. Both papers found task deficits in working memory and behavioral flexibility, which are commonly found in human schizophrenia patients.             Kellendork  et al.  began with a dopamine hypothesis of schizophrenia, ...

Moore et al. focused on the existing hypothesis that schizophrenia is a result of abnormal brain development, particularly in frontal and limbic cortical circuits and dopaminergic inputs to the striatum. The current study used MAM to disrupt development of E15 and E17 mice, focusing on the effect on the morphology of paralimbic frontal/temporal cortices and medial dorsal/midline thalamic nuclei. Furthermore, corticostriatal circuit function was analyzed to extend research on cognitive deficits in MAM-E17 mice. MAM decreased brain weight and universal brain region size in both E15 and E17 groups, even though the MAM-E17 group showed no change in number of cells. MAM-E17 showed a more schizophrenic-like decrease in grey matter and an increase in density in the prefrontal/cingulate and insular/perirhinal zones. These neurons in the prefrontal cortex showed a more depolarized resting potential and spike threshold, and the average spike threshold was more depolarized. Behavioral abnormal...

That over-expression of D2 receptors in the striatum would cause cognitive deficits related to expression of receptors during the developmental time line, rather than consistent dopamine elevated release, is a fascinating point. I had always been interested in the comparative effects between either increasing concentration of a neurotransmitter or increasing the concentration of receptors for a neurotransmitter and leaving its basal concentration the same. On the one hand, you have more bioavailability to reach receptor targets, while on the other hand you have greater surface area distribution of receptors that can cause activation. One might assume that the results of these processes are the same, and yet the Kellendonk paper shows that there is indeed a difference between the two. Perhaps the very reason that classical antipsychotics, which are D2 receptor antagonists, display only moderate effectiveness, is because schizophrenics already have such a high distribution of dopamine ...

The papers this week focus on creating relevant models for schizophrenia. Kellendonk et al . produced a mouse model using transgenic means that had over expression of the D2 receptor in the striatum, this was relevant due to the notion that most effective anti-psychotics (treating positive symptoms) are D2 receptor antagonists. Moore et al. created a developmental animal model by injecting the methylation agent methylazoxymethanol acetate (MAM) into dams on E17 which produced mice with abnormal development of the frontal and limbic cortical circuits and and abnormal dopamine (DA) input to the striatum. I thought Moore et al’s findings were very interesting especially the inclusion of cerebral cortex abnormalities which are absent from other models of schizophrenia such as the neonatal hippocampal lesion model and the chronic phencyclidine model. The inclusion of this symptom seems very significant because as seen in the study and in those with schizophrenia, a decrease in ...

Published in the same year, our two papers this week focused on two different models of schizophrenia in mice. Kellendonk et al. (2006) used a pharmacological lens, in their exploration of the DA hypothesis, which posits that an excess number of dopamine receptors, or over-sensitive receptors contributes to the pathology of schizophrenia. On the other hand, Moore et al. (2006) argues for a more developmental model using MAM, critically at the 17th day of embryonic development.  It was acknowledged in Kellendonk et al. that drugs commonly used to treat schizophrenia are antipsychotics that block D2 receptors. However, these drugs only seem to improve positive symptoms. So to determine whether or not there is a causal relationship between D2 receptors and negative symptoms (cognitive deficits), researchers used transgenic mice that overexpressed D2R in the striatum. But if there is a significant relationship then why don’t we see significant effects in patients with schizophrenia...

Kellendonk et al. and Moore et al. developed two distinct rodent models of schizophrenia that both incorporate disruption of normal embryonic development. Kellendonk et al. developed a double-transgenic mouse line in which tet-off dopamine-2 receptors (D2Rs) are reversibly overexpressed in the striatum, a region implicated in schizophrenia pathophysiology. They cite studies dating back to Arvid Carlsson's 1963 dopamine hypothesis of schizophrenia, many of which associate aberrant dopamine transmission in the striatum and prefrontal cortex with schizophrenia. Moore et al. delivered the cytostatic agent MAM to timed-pregnant rat dams at embryonic day 17, during which cortical structures are still developing but subcortical and cerebellar structures are all set. They developed this model based on evidence for the role of abnormal development of frontal and limbic cortical circuits in schizophrenic basal ganglia and dopaminergic systems. They suggest that MAM-induced DNA methylatio...

Sial et al., 2015 introduced the vicarious defeat stress model (VSDS) to help separate the influence of physical stressors from emotional stressors. Instead of measuring the effects of social defeat on mice, the VSDS measures the effects of observing other mice experiencing social defeat. This includes a witness component and theoretically helps separate psychological stress from physical stress in mice. Both emotional and physical stress decrease weight gain, more so with emotional stress. However, these measures returned to baseline within a couple days. Mice were then tested with the social interaction test and elevated plus-maze. Both PS and ES resulted in social avoidance and reduced time in the open arms of the maze. Fluoxetine injections reversed induced phenotypes in both groups over 30 days, not after a single injection. Allsop et al., 2018 used several experimental groups to study observational learning in mice and how it relates to the BLA and ACC. They wanted to answer ...

The Sial et al. paper was relatively easy to read and understand compared to the other recent papers we have been breaking down, but still holds many interesting insights into how to overcome the etiologically irrelevance of many PTSD or depressive measures, and overall how we can better model observational PTSD in mice for insights into human psychology. Although the Sial group convincingly demonstrates that emotional stress (ES) has similar effects on daily weight gain, serum cortisol levels, time spent in open arms of the elevated plus-maze test, and social interaction as physical stress (PS) in mice, I was concerned about the data presented on their reversal of these symptoms with chronic fluoxetine administration. Sial et al. present significant reversal of social interaction effects of emotionally and physically stressed mice after 1 month of fluoxetine treatment, but their error bars are quite large, especially in the fluoxetine treated PS group. I can attribute this to how ant...

I found the second paper wholly impressive in its use of opto-genetics to inhibit the ACC->BLA circuit. The presentation of data was very complex in comparing the cue response neurons that changed frequency for the ACC and the BLA. I found it very interesting that they used a comprehensive pie chart to show whether the population of neurons that responded to a cue were excited or inhibited. It was interesting to note that a cue response will activate small proportion of neuronal ensemble in the ACC even when it is not paired with a fearful event. To me, this shows that the ACC encodes broad range of stimuli, and when fear is a component, it recruits a greater amount of excitatory neuronal ensemble. Lesions in the anterior-cingulate cortex have been noted to cause negative changes in mood and irritability. It is possible that a cue caused a small disturbance and thus a very small ensemble of excitatory neurons became recruited. Another interesting facet of the paper highlighted the f...

            Observational fear learning is an innate social behavior, Allsop et al. 2018 outlines the neural circuit underlying how the brain encodes emotionally salient (fear) behavior with neutral cues associated through observational fear learning. Allsop et al, found that projections from the Anterior cingulate cortex (ACC) to the Basolateral Amygdala (BLA) are essential in encoding observational learning. Specifically observing distress causes basal changes in the ACC neurons (encoding of the observed behavior through social cues) which enables the acquisition of the predictive nature of the aversive cue by BLA neurons. When ACC - BLA projections were optogenetically inhibited while mice were observing fear conditioning a reduced freezing response was seen when conditioned fear response was tested. Interestingly when the ACC - BLA projections were inhibited during testing of observational fear conditioning the...