The Effects of Schizophrenia on Cognitive Mapping

Post by Christopher Chen 

The takeaway

We use cognitive maps to help make sense of the world, but these maps might be distorted and disorganized in people with schizophrenia (PScz). Researchers discovered that the reduced influence of semantic similarity and abnormal hippocampal ripples (i.e. transient bursts of high-frequency activity) in PScz contribute to cognitive disorganization found in PScz. 

What's the science?

Schizophrenia is a prevalent neuropsychiatric disorder causing conceptual disorganization, abstract reasoning difficulties, and language coherence issues. The presence of these symptoms, collectively known as "formal thought disorder," predicts impaired social functioning. Schizophrenia is also associated with abnormalities in association-guided cognition, where relationships between memories, concepts, or objects in the brain, known as "relational knowledge," are disrupted.

Recent studies suggest that the hippocampal–entorhinal cortex (HEC) encodes abstract relational knowledge. In rodents, researchers have shown that HEC cells encode spatial relationships during navigation of the environment and exhibit neural "replay" during rest. In humans, the HEC also encodes associations in abstract domains, supporting a domain-general "cognitive mapping" function that spans conceptual and semantic spaces. Furthermore, hippocampal ripple power, a neural output linked to cognitive map stabilization, is known to be disrupted in PScz. However, the impact of schizophrenia on cognitive maps as well as the neural signatures of these outputs are unknown. In a recent article in PNAS by Nour et al., researchers used a combination of verbal fluency analysis and brain imaging to help fill gaps in understanding the impact of schizophrenia on cognitive mapping. 

How did they do it?

To assess verbal fluency, 52 participants (26 PScz and 26 controls) were given 2 separate language-based tests, each 5 minutes long. For the first test, they were asked to name as many animals as they could in the allotted time (category fluency), while in the second test, they were asked to name as many words as they could that started with the letter "p" (letter fluency). 

Researchers used several analysis tools, including a novel Natural Language Processing (NLP) machine learning approach, to measure semantic associations (i.e. similarities) between the words each patient provided. The researchers then measured how closely participants' word sequences approximated the “optimal path” of word sequences generated by mathematical algorithms, with greater divergences from the optimal path metrics suggesting “looser” conceptual organization. 

Researchers were also interested in investigating how neural signatures associated with verbal fluency manifested in PScz. To do so, researchers used a brain imaging technique called magnetoencephalography (MEG) to characterize brain activity in participants following verbal learned task sequences. Specifically, MEG data were collected from participants who had completed a sequence learning task and were resting quietly, to reveal whole-brain activity patterns of spontaneous neural replay of those learned task sequences.  

What did they find?

PScz showed less optimal word selection over time during the category fluency task, suggesting that their cognitive processes were more disorganized. Additionally, computational modeling demonstrated that the balance between category and letter-based information in task performance was notably influenced by the task goal (context). In other words, category-based (semantic) bias was seen in the animal-naming task while letter-based bias (similarity between words, letter by letter) was seen in the ‘p’ word task. The extent of this influence, referred to as "goal-induced semantic modulation," was significantly reduced in individuals with schizophrenia, again suggesting that PScz exhibits an impairment in how semantic information is used to guide the flow of thought. Furthermore, greater variability in goal-induced semantic modulation across participants correlated with greater difficulty with abstract conceptual reasoning, which is considered to be a “negative” symptom in schizophrenia. This suggests that the observed deficits in goal-induced semantic modulation may be linked to specific symptoms in schizophrenia, providing valuable insights into the cognitive mechanisms underlying the disorder.

As for brain imaging data, MEG traces showed that in both controls and PScz, participants with greater ripple power at the time of replay demonstrated a greater tendency to use semantic information for context-sensitive word selection. Essentially, greater ripple power was correlated with greater cognitive organization during verbal fluency behavior. Interestingly, the study did not find a correlation between goal-induced semantic modulation and a previously reported measure of spontaneous replay, providing valuable insights into the nuanced relationship between neural processes and semantic cognition in individuals with schizophrenia.

What's the impact?

This study provided preliminary support for the hypothesis that some symptoms of schizophrenia are linked to dysfunction in cognitive maps. Overall, these findings are some of the first to connect clinical features of schizophrenia to the neural processes underlying abnormalities in semantically guided cognition.

Neurogenesis During Pregnancy Influences Maternal Behavior

Post by Laura Maile 

The takeaway

Adult neural stem cells (NSCs) contribute to brain plasticity throughout life. During different phases of pregnancy, NSCs differentiate into distinct subtypes of olfactory bulb neurons, influencing maternal behavior. 

What's the science?

The adult mouse brain contains stem cells that are influenced by environmental changes and can differentiate into distinct cell types. Physiological states such as hunger and satiety are known to influence specific regional populations of adult NSCs. Pregnancy induces changes in several brain areas including the ventricular subventricular zone (V-SVZ), which contains neural stem cells (NSCs) that differentiate into olfactory bulb neurons and show increased proliferation at certain stages of pregnancy. It’s unknown, however, whether pregnancy and other physiological states can control specific populations of NSCs and whether there’s a functional outcome on brain plasticity and behavior. This week in Science, Chaker and colleagues investigated how distinct neural stem cells respond to pregnancy to produce specific olfactory bulb neurons that influence the behavior of mothers around the time of birth. 

How did they do it?

Using GFAP and Ki67 in mice, the authors labeled and quantified proliferating NSCs in the V-SVZ on different days of gestation and post-pregnancy. Next, they injected pregnant females with a thymidine analog on specific days of pregnancy to label newly born neurons and then analyzed their olfactory bulbs three weeks later when the labeled neurons would be integrated. This allowed them to determine whether specific populations of NSCs differentiate into distinct cell layers and subtypes of olfactory bulb neurons. To understand whether the newly differentiated olfactory bulb neurons were long-lasting past weaning (i.e., when the mice are separated from the mother), they quantified the surviving cells again 30 days post analog injection. They next performed spatial transcriptomics to characterize the genetic profiles of olfactory bulb layers that experience neurogenesis (i.e., growth of new neurons) during and after pregnancy. They then focused on one cluster that was enriched in mothers during pregnancy to determine what neuronal markers were associated with pregnancy. To determine the function of the transiently increased pregnancy-associated neurons, the authors measured their survival when maternal care was disrupted by prematurely removing pups, cross-fostering with new pups, or exposing mothers or virgin mice to pup nest odor. Finally, they conducted olfactory behavior tests in mothers during pregnancy who had specific populations of olfactory bulb interneurons depleted or maintained. 

What did they find?

The authors discovered that distinct regions of the V-SVZ showed activity and proliferation on specific days during pregnancy. This indicates that there are both temporally and spatially dynamic patterns of differentiation controlled by the phase of pregnancy of the adult mouse.  After injecting a thymidine analog on specific gestation days, they found that pregnancy induces neurogenesis in discrete sublayers of the olfactory bulb and that these new neurons become functionally integrated into the existing circuitry. Once pups began feeding on solid food and required less maternal care, however, the olfactory bulb showed decreased numbers of these newborn neurons, and nearly all of them disappeared by weaning. This confirms that pregnancy induces transient neurogenesis at specific stages of the perinatal period. Spatial transcriptomics revealed clusters of neurons corresponding to olfactory bulb layers, that showed upregulation in certain genes at specific time points, indicating the spatial and temporal control of neurogenesis in response to pregnancy.

When pups were removed from maternal care prematurely, certain interneurons were correspondingly lost early. Similarly, when cross-fostering with news pups, some pregnancy-related interneurons survived, while others were lost. The neurons lost shared genetic profiles and location in olfactory layers. Additionally, specific interneuron populations were rescued when mothers were exposed to new pup nest odor, and others were not, indicating the necessity of pup odor for the survival of pregnancy-related neurons. Loss of one type of pregnancy-related interneuron reduced the ability of mothers to discriminate between their own pups and new pups. This shows that pregnancy-related neurogenesis is important for own pup odor recognition, but not for general olfactory function. Loss of different types of interneurons decreased pup exploration index, suggesting that pregnancy-related neurogenesis is important for pup odor sensitivity during early motherhood. 

What's the impact?

This study demonstrated that neural stem cells can generate specific populations of neurons to help pregnant mothers prepare for maternal care. Different physiological states, such as hunger, satiety, and pregnancy, can influence adult neurogenesis to suit transient needs and influence behavior, according to environmental and physiological changes. 

Access the original scientific publication here. 

The Relationship Between Sleep, Circadian Rhythms, and Neuronal Myelination

Post by Meredith McCarty 

The takeaway

Myelination is pivotal for neuronal function and is altered in many neurodegenerative disorders including multiple sclerosis (MS). In this study, the authors find that myelination development and maintenance are dependent on the circadian transcription factor Bmal1. 

What's the science?

Myelination is the process by which neurons are encased in a myelin sheath, providing metabolic support and increased signaling efficiency of the neuron. Myelination is maintained by oligodendrocyte cells, which produce myelin sheaths for neurons throughout the central nervous system. Oligodendrocyte precursor cells (OPCs) are the precursor for oligodendrocytes, yet not much is known about their development and regulation. 

Bmal1 is a transcription factor involved in circadian rhythm regulation, and recent research has found the disruption of Bmal1 to be correlated with changes in OPC function. This week in Neuron, Rojo and colleagues investigate the role of Bmal1 in myelination processes, and how these dynamics are related to sleep disruption and circadian cycles. 

How did they do it?

To study the relationship between circadian rhythms, Bmal1 dynamics, and myelination throughout development, the authors conducted several genetic and behavioral experiments in mouse models. 

The mouse models used in this study were wild-type (i.e., normal) mice and mice that had the Bmal1 transcription factor knocked out from the OPC cells specifically (OPC-specific Bmal1 knockout mice). To quantify changes in OPC proliferation at different experimental time points, the authors injected a tag to measure DNA proliferation called EdU. To understand the role of Bmal1 in OPC regulation, the authors performed RNA-sequencing and circadian rhythmicity assessment on OPC cells from mice at varying experimental time points. The authors then quantified physical changes in myelination throughout the central nervous system using transmission electron microscopy (TEM) as well as tests of the integrity of the blood-brain barrier in wild-type and mice without Bmal1. 

To quantify changes in mouse behavior, the authors used measures of gait, stride length, and working memory. To study the role of sleep deprivation in Bmal1 function, the authors altered the mouse sleep/wake cycles and recorded during wake and sleep from implanted EEG electrodes. To probe the regulation of remyelination during adulthood, the authors quantified morphological complexity in older mice and performed a focal demyelination procedure in wild-type mice and mice without Bmal1. Lastly, the authors analyzed human genetic data to study the relationship between the risk of MS and sleep fragmentation. 

What did they find?

The authors found changes in OPC proliferation depending on the circadian rhythm. Additionally, mice without Bmal1 exhibited decreased OPC density and physical complexity in the corpus callosum (the white matter connecting the left and right hemispheres of the brain), but not in other brain regions. The authors also found a significant reduction in OPCs throughout cortical and subcortical brain regions in the developing brains of mice without Bmal1, suggesting reduced OPC migration in these mice. The authors next used RNA sequencing to compare genes expressed in OPCs at different time points in the circadian cycle and found that 10% of genes were rhythmically expressed in OPCs. This suggests that Bmal1 regulates OPC dynamics in specific brain regions at specific points in development and during the circadian rhythm. 

When measuring changes in myelination using transmission electron microscopy (TEM), the authors found the corpus callosum to have thinner myelination in mice without Bmal1 relative to wild-type mice. The authors found no differences in the integrity of the blood-brain barrier in mice without Bmal1-KO. Next, when the authors used a novel object recognition task to assess whether these changes in myelination altered the behavior of mice without Bmal1, they found deficits in working memory, stride length, and gait. suggesting that Bmal1 disruption and altered myelination results in behavioral and cognitive effects.  

EEG recordings during sleep deprivation experiments revealed mice without Bmal1  exhibited disrupted sleep and altered recovery from sleep deprivation relative to wild-type mice. The authors next compared the effect of Bmal1 disruption in early versus later developmental time points, quantifying changes in OPC morphology and migration. They found that Bmal1 knockout in adolescence led to significant disruption of OPC density and complexity. Interestingly, Bmal1 knockout in adulthood led to disrupted remyelination, but no changes in OPC density. 

What's the impact?

In this study, the authors find that Bmal1 regulation is tightly linked with circadian rhythms and the maintenance of myelination throughout specific regions of the mouse central nervous system. Interestingly, the authors note that since sleep disruption is associated with an increased risk of MS in humans, this novel evidence has implications for the treatment of demyelinating disorders like MS. Future research is necessary to clarify the relationship between MS and sleep in human studies.

Access the original scientific publication here.