Effects of Stress on Learning and Memory Processes

Psychologically stressful events evoke a long-term impact on behavior through changes in hippocampal function. These changes in glutamatergic, GABAergic, and glucocorticoid hormone signaling lead to altered regulation of gene transcription. Specifically, these epigenetic changes moderate the ERK/MAPK signaling pathway and the induction of c-fos and egr-1 genes.

Without memory, we could not function as human beings. We need memories to understand our environment and make decisions based on past knowledge. The hippocampus is an important brain region for memory formation. It’s vital for the consolidation of contextual memories. During stressful events, there is an increase in the secretion of glucocorticoid hormones (i.e. cortisol) that enhances memory formation in the hippocampus. The hypothalamus’s dentate gyrus (DG) is another important brain region involved in memory formation. The glucocorticoid receptors (GRs) in the dentate gyrus were found to be involved in the consolidation of adaptive responses based on memories of initial experiences.

In stressful events, we often form strong memories, however not all stressful events incapacitate people and keep them from their daily lives. So, why does 10% of the population develop PTSD? When people cannot adapt and cope after stressful events, they can develop an anxiety disorder like post-traumatic stress disorder (PTSD).

Figure 1. How stress affects our regulation of cortisol and impacts memory formation (3).

A Signaling Pathway Involved in Learning and Memory Processes

Calcium activates the NMDA receptor and mediates the ERK-MAPK signaling pathway. The activated ERK pathway helps form the dual histone marks in the DG granule neurons. When GRs are activated, they act like scaffold proteins for the ERK pathway), pERK1/2 then phosphorylates MSK1/2 and Elk-1. MSK phosphorylates serine (S10) and Elk-1 acetylates lysine (K14) of histone (H3) molecules within the c-fos and egr1 gene promoters. These modifications make histones less positive which causes DNA to unwind from them, allowing transcription factors to bind. Histone modifications and chromatin opening are needed to provide transcription factors access to their DNA binding sites.

Figure 2. Psychological stress-activated signaling pathways in dentate gyrus granule neurons drive epigenetic modifications underlying the induction of gene transcription and the consolidation of behavioral responses and memory formation in the hippocampus (1).

Epigenetics

Epigenetics is the study of how your behaviors and environment can cause changes that affect the way your genes work. Epigenetic changes that occur as a result of stressful events cause an increase in dual histone marks (H3S10p-K14ac). These dual histone marks are hypothesized to open chromatin’s structure by unraveling the histones from DNA so that transcription factors can bind to previously silent genes and IEG promoters. Immediate-early genes (IEGs) are crucial for memory formation, like c-fos and egr-1.

Nothing in Anxiety Disorders like PTSD makes sense, except in the light of stress-driven increases in dual histone marks and IEGs.

GABAergic Tone

The GABAergic system, known for its role in regulating anxiety states, influences the responsiveness of granule neurons in the DG to psychological stress. High anxiety levels are associated with low GABA activity, which can lead to debilitating effects. Balancing excitatory and inhibitory inputs is crucial for maintaining healthy information flow in brain circuits.

Figure 3. An imbalance of excitatory and inhibitory neurotransmission can lead to anxiety (2).

How do Strong Memories of Stressful Events Turn into PTSD?

When a stressful event overwhelms a person’s coping mechanisms, it can lead to the formation of strong memories. Overactive signaling pathways involving NMDARs, GRs, ERK/MAPK, MSK, and Elk-1 contribute to heightened stress responses and the consolidation of these memories. Higher levels of anxiety can further strengthen these memories and increase the likelihood of maladaptive responses to future stressful events.

Stressful situations have a profound impact on memory formation, often resulting in strong memories that can lead to anxiety disorders like PTSD. Understanding the intricate mechanisms involved, from epigenetic changes to neurotransmitter dynamics, is crucial for developing targeted interventions and therapies to support individuals affected by these conditions.

Figure 4. PTSD vs Anxiety (4).

References

Addiction

Artstract. Art found online that I believe depicts the detrimental impact psychostimulant drug use has on our brains.

Psychostimulant Use Disorder

Psychostimulant Use Disorder (PUD) causes changes in the brain’s reward circuit and glutamatergic neurotransmission. Because amphetamine-like psychostimulants have a similar structure (phenylalkylamines) to the endogenous catecholamine neurotransmitters (norepinephrine, epinephrine, and dopamine), psychostimulants are theorized to alter catecholamine neurotransmission. These changes lead to dopamine-driven reinforcement and drug-seeking behaviors (1).

Nothing in PUD makes sense, except in the light of altered brain neuroplasticity.

Figure 1. Psychostimulant structure compared to catecholamine neurotransmitters (2).

Psychostimulants

Psychostimulants are drugs that increase (“stimulate”) the CNS. They bind to extracellular catecholamine receptors (i.e. DA) to promote the release of neurotransmitters (NTs). They can also suppress monoamine NT reuptake and oxidase metabolism, which leads to elevated levels of NTs in the synapse.

Glutamate

Glutamate is the primary excitatory neurotransmitter in the central nervous system. Modulating glutamate neurotransmission has emerged as a promising approach for treating cognitive deficits associated with substance use disorders (SUDs), including PUD. When glutamate is released from presynaptic neurons, it diffuses through the synapse and binds to various glutamate receptors including ionotropic (such as NMDA and AMPA) receptors that are fast-acting and crucial for brain plasticity as well as metabotropic receptors. Metabotropic glutamate receptors are categorized into three groups:

Group 1

• mGluR1 & mGluR5
• postsynaptic
• Gq-coupled.

Group 2

• mGluR2 & mGluR3
• presynaptic
• Gi-coupled.

Group 3

• mGluR4 & mGluR6 & mGluR7 & mGluR8
• presynaptic
• Gi-coupled.

Figure 2. Distribution of mGluRs in the Brain’s Reward Circuit (1).

Neurocircuitry of SUDs: The Brain’s Reward Circuit

The reward circuit involves intricate interactions between dopaminergic projections from the ventral tegmental area (VTA), glutamatergic and GABAergic neurotransmission, and brain regions like the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc).

Dopamine activity in the brain is modulated by the VTA brain region. In reward processing and drug-seeking behaviors, glutamatergic neurons from the mPFC stimulate the VTA’s dopaminergic neurons to release dopamine in the NAc (1).

Figure 3. VTA plays an important role in the brain’s reward circuit (3).

Neuroplasticity and Memory Formation in PUD:

Alterations in synaptic strength, dendritic morphology, and receptor expressions are found in neurons associated with the brain’s reward circuits. Long-term potentiation (LTP) and long-term depression (LTD) in glutamate synapses, particularly in the hippocampus and mesocorticolimbic pathways play a crucial role in the altered neuroplasticity that comes from drug abuse.

Group 1 mGluRs have been found to affect synaptic plasticity in reward circuit brain regions in PUD cases. They modulate short- and long-term synaptic plasticity, including LTD, through intracellular signaling pathways involving phospholipase C (PLC) that increase learning, memory, and LTP. mGluR1 is thought to be involved in the acquisition process while mGluR5 has a role in retaining and maintaining spatial memories. Because group 1 mGluRs are located on the postsynaptic neuron, antagonist drug treatments have been found to reduce drug-seeking behaviors by blocking the reward signal from being passed on (1).

Figure 4. Antagonist drug treatments have been found to reduce addiction when targeting Group 1 receptors because they inhibit mGluRs on the postsynaptic cell.

Group 2 mGluRs negatively regulate glutamate release and are necessary for inducing LTD in the reward circuit. Because group 2 mGluRs are located on the presynaptic neuron, agonist drug treatments have been found to reduce drug-seeking behaviors by stimulating auto receptors to decrease the number of neurotransmitters released in the synapse (1). Group 3 mGluR’s role in PUD synaptic plasticity needs to be studied further, particularly mGluR7 and 8 in regions like the NAc, VP (striatum), and the hypothalamus.

Figure 5. Agonist drug treatments have been found to reduce addiction when targeting Group 2 receptors because they stimulate the mGluR auto receptors that self-regulate by reducing NT release.

Questions to Think About…

• Does the altered brain chemistry from addiction ever go back to the way it was?
• Can we unlearn memory/ the motivated driver of addiction?

References

What is Schizophrenia?

Schizophrenia is a psychiatric disorder that is more common than most think. It is characterized by psychotic or positive symptoms that may include delusions, hallucinations, disorganized speech, and cognitive impairment. Typically, this disorder is diagnosed in late adolescence. However, little is known regarding the biological etiology of it. An article by Singh describes the possible underlying genetic risk factors, specifically within the Wnt and glycogen synthase kinase 3 (GSK3) pathway. The issue that they present is overactive GSK3, which ultimately leads to less β-Catenin.

Many factors may contribute to hyperactive GSK3 such as inhibitory phosphorylation of AKT due to increased dopamine receptor activation or increased activation of metabotropic glutamate receptors. Moreover, there are specific genes that have been associated with Schizophrenia like DISC1, which has been found to be deleted in this disorder. This was the first risk gene studied followed by Akt and copy number variations.

All of this goes to show the complexity of Schizophrenia, which raises the question of how we might be able to better treat these individuals. However, treatment must start with assessment, which is more difficult with people who may not know the symptoms or severity of the disorder that they are dealing with. One type of assessment that professionals might begin with includes measures for cognitive function and insight.

Measures of cognitive ability

Studies displayed in an article by Haddad et al. have shown that many patients with Schizophrenia that display severe cognitive impairments do not report those deficits nor have awareness of their cognitive function. Therefore, a number of clinicians utilize neuropsychological assessments instead of self-report measures in these cases. Overall cognitive function typically assesses at least five different categories of abilities which are shown in figure 1. Some others specify what they are looking for such as overall symptoms or insight.

Figure 1. Level of importance in cognitive ability categories [1]

While each assessment for cognitive ability covers similar subscales, each one is specialized for specific questions and situations, which are categorized in figure 2. Shown below are some examples of this.

Assessments primarily for cognition

The brief assessment of cognition in schizophrenia (BACS): 30 minute, pen and paper, neuropsychological battery used to assess cognitive abilities in schizophrenia. This battery contains 6 subscales: verbal memory, digit sequencing (working memory), token motor task (psychomotor function), semantic fluency (verbal fluency), symbol coding (attention and processing), and Tower of London (executive function). Originally, it was developed for clinical trials with key features of portability, repeatability, and multiple forms [2].

The Self-assessment scale of cognitive complaints (SASCCS): Self-report instrument that investigates how patients perceive their cognitive impairment through 21-items on memory, attention, executive functions, language, and praxia. This instrument utilizes a 5-point likert type scale to evaluate symptoms (0=never, 4=very often) [3].

Figure 2. Subcategories of cognitive and diagnostic assessments [4]

Assessments for other specified questions

The Positive and Negative Syndrome Scale (PANSS): 30-item questionnaire to evaluate clinical symptoms based on 3 subscales, positive and negative symptoms and overall psychopathology [5].

Insight Scale for Psychosis (IS): self-report survey that measures the patient’s insight levels with 8 questions divided into 3 subscales:  awareness of illness, re-labeling of symptoms, need for treatment. The higher the score, the greater insight the patient has. Individuals with Schizophrenia may be able to estimate cognitive impairment independent of their level of insight [5].

Conclusion

With the changing and advancing scientific background behind psychiatric disorders such as Schizophrenia, it is important to continue to change evaluations and treatments to match our knowledge. One way to do this in schizophrenia specifically is through cognitive assessment. This is vital in this disorder because having an understanding of the patients cognitive impairment as well as their insight into their symptoms will help professionals find a treatment that works best for them.

References 

[1] Gebreegziabhere, Y., Habatmu, K., Mihretu, A., Cella, M., & Alem, A. (2022). Cognitive impairment in people with schizophrenia: An umbrella review. European Archives of Psychiatry and Clinical Neuroscience, 272(7), 1139–1155. https://doi.org/10.1007/s00406-022-01416-6

[2] Keefe, R. S. E., Goldberg, T. E., Harvey, P. D., Gold, J. M., Poe, M. P., & Coughenour, L. (2004). The Brief Assessment of Cognition in Schizophrenia: Reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophrenia Research, 68(2), 283–297. https://doi.org/10.1016/j.schres.2003.09.011

[3] Haddad, C., Sacre, H., Abboche, E., Salameh, P., & Calvet, B. (2023). The self-assessment scale of cognitive complaints in Schizophrenia: Validation of the Arabic version among a sample of lebanese patients. BMC Psychiatry, 23(1), 415. https://doi.org/10.1186/s12888-023-04925-3

[4] Sandy. (2013, May 15). Cognition in schizophrenia and bipolar disorder. NeuRA Library. https://library.neura.edu.au/schizophrenia/signs-and-symptoms/cognition/schizophrenia-vs-bipolar/

[5] Birchwood, M., Smith, J., Drury, V., Healy, J., Macmillan, F., & Slade, M. (1994). A self-report Insight Scale for psychosis: Reliability, validity and sensitivity to change. Acta Psychiatrica Scandinavica, 89(1), 62–67. https://doi.org/10.1111/j.1600-0447.1994.tb01487.x

Picture 1: Possible pathology, and treatment for schizophrenia[1].

Schizophrenia is a chronic brain disorder, which affects about 1 % of the U.S. population[2]. The symptoms that characterize the disorder can be fall into the categorizes of positive and negative symptoms. Positive symptoms are abnormally present, and can be hallucinations, paranoia and exaggerated or distorted perception, beliefs, and behaviors[3]. While negative symptoms concern what is abnormally absent such as the loss or decrease in ability to speak, express emotion, initiate plans and find pleasure[4].

There is no cure for the disorder, and there has yet to be found a cause or the pathology or the biological bases for how schizophrenia develops. A possible pathway that plays a role and can be correlated with schizophrenia is the wnt signaling pathway. The wnt signaling pathway play a role in neural development in addition to neural circuit function[5]. In relation to schizophrenia there can be understood to be overactivation of GSK-3β, which causes a decrease in β-catenin levels[6]. In the wnt pathway, if there is proper signaling GSK-3β levels are down, while β-catenin levels are increased[7], seen in Figure 1, is the explanation of this process. β -catenin is required for TCF/LEF transcription.[8] Transcription is the process of making RNA from a gene’s DNA sequence[9]. Together β-catenin and TCF/LEF transcription is important for schizophrenia and can be a factor in the development of schizophrenia.

Figure 1: GSK-3β is a part of a destruction complex that keeps β -catenin phosphorylated, which causes the deceased levels of β -catenin. However, when Wnt binds to the receptor which facilitates disengagement of the destruction complex, it decreases the phosphorylation that results in β -catenin being able to transfer into the nucleus[11].

Treatment

Picture 2: The different components in treating schizophrenia[12].

There is no treatment found that treats all the symptoms present in schizophrenia patients, which makes the treatment of the disorder a bigger process, of multiple components. As seen in figure 2, a combination of medications, and nonpharmacological treatment, like psychotherapy, and patient compliance can have an effect in treating the disorder[13].

Medication is the first process in treatment of schizophrenia, and the most typical used is antipsychotics. These drugs bind dopamine receptors, which can relate to the possible hyperactivity in dopamine levels in patient with schizophrenia. In dopamine hyperactivity there are higher levels of GSK-3β, and a deceased amount of β-catenin, which can correlate to the function of the wnt signaling pathway[14]. The antipsychotics predominantly target the positive symptoms related to schizophrenia, while having limited effect on the negative symptoms.

Patient compliance is another important factor in the treatment of the disorder, this concerns ensuring patient are taking their medications. Nonpharmacological therapies therapies can help to ensure that patients remain adherent to their medications[15].

There are various other treatment such as cognitive behavioral therapy[16], transcranial magnetic stimulation[17], and yoga therapy[18]. Nonpharmacological treatments should be used as an addition to medications, not as a substitute for them[19]. Treatment programs in which encourage family support have shown to decrease rehospitalization and to improve social functioning for patient with schizophrenia[20].

There needs to be further research to improve the quality of treatment, and understanding the pathology of the disorder in more detail. In combination, a conversation talking about the ethics of treatment, and how it affects schizophrenia patients should be encouraged.

Bibliography

Aleman, A., Enriquez-Geppert, S., Knegtering, H., & Dlabac-de Lange, J. J. (2018). Moderate effects of noninvasive brain stimulation of the frontal cortex for improving negative symptoms in schizophrenia: Meta-analysis of controlled trials. Neuroscience & Biobehavioral

Ganguly, P., Soliman, A., & Moustafa, A. A. (2018). Holistic Management of Schizophrenia Symptoms Using Pharmacological and Non-pharmacological Treatment. Frontiers in public health, 6, 166. https://doi.org/10.3389/fpubh.2018.00166

Lodha, P., & De Sousa, A. (2020). Cognitive behavioural therapy and its role in the outcome and recovery from schizophrenia. In A. Shrivastava & A. De Sousa (Eds.), Schizophrenia treatment outcomes: An evidence-based approach to recovery (pp. 299–312). Springer Nature Switzerland AG. https://doi.org/10.1007/978-3-030-19847-3_26

Lpc/Mhsp, J. C. M. (2023, May 29). How schizophrenia is treated. Verywell Mind. https://www.verywellmind.com/schizophrenia-treatments-2330662

Ocampo, T. (2023, January 30). Understanding schizophrenia – Medical Channel Asia. Medical Channel Asia. https://medicalchannelasia.com/understanding-schizophrenia/

Patel, K. R., Cherian, J., Gohil, K., & Atkinson, D. (2014). Schizophrenia: overview and treatment options. P & T : a peer-reviewed journal for formulary management, 39(9), 638–645.

Singh K. K. (2013). An emerging role for Wnt and GSK3 signaling pathways in schizophrenia. Clinical genetics, 83(6), 511–517. https://doi.org/10.1111/cge.12111

Transcription. (n.d.). Genome.gov. https://www.genome.gov/geneticsglossary/Transcription#:~:text=Transcription%2C%20as%20related%20to%20genomics,protein%20information%20encoded%20in%20DNA.

What is Schizophrenia? (n.d.). https://www.psychiatry.org/patients-families/schizophrenia/what-is-schizophrenia