3.8.2 Neurodevelopmental models of psychiatric disorders

Neurodevelopmental Models of Psychiatric Disorders

Depression:

Depression, often known as major depressive disorder (MDD), is characterized by a constant poor mood, social disengagement, lethargy, cognitive decline, anxiety, and low energy. Depression is hypothesized to be influenced by genetic, developmental, immunological, stressful, social, and environmental variables.

Early life stress and social rejection are two factors that might cause behavioural and cognitive abnormalities that resemble MDD. The social defeat model in particular causes altered cognition, social behaviour, and anxiety in rats and is susceptible to the antidepressants now recommended for depression.

Examples of animal models used in understanding depression:

Model:	Summary:
Forced swim test (Posolt)	Antidepressants acutely increased the time an animal struggles in a chamber of water with no access to a platform. Lack of struggle is thought to represent a state of despair in mice.
Tail suspension test	Antidepressants acutely increased the time an animal struggles when suspended by its tail. Lack of struggle is thought to represent a state of despair.
Learned helplessness	Animals exposed to inescapable footshock take a longer time to escape, when subsequently exposed to an escapable foot shock. Antidepressants acutely decrease escape latency and failures.
Social stress	Animals exposed to different types of social stress show behavioural abnormalities.
Early life stress	Animals separated from their mothers at a young age demonstrated persisting behaviour and HPA axis abnormalities as adults.
Fear conditioning	Animals demonstrated fear-like responses when exposed to previously neutral or context-dependent cues that were aversive.
Yoked shock test	One of the first experiments of ‘learned helplessness’ was with groups of dogs: one being controls and another given an electric shock for which they had to escape. From these experiments, it was thought that there was to be only one cure for helplessness. In Seligman’s hypothesis, the dogs do not try to escape because they expect that nothing they do will stop the shock.
Olfactory bulbectomy	Chemical or surgical lesions of the olfactory bulb cause behavioural abnormalities, some of which can be reversed by antidepressant treatments.

(Nestler, 2002)

Schizophrenia:

Schizophrenia is a complex psychiatric disorder characterized by symptoms such as delusions, hallucinations, disordered thinking, and negative symptoms. A number of neurodevelopmental models have been proposed to explain the underlying pathophysiology of schizophrenia. These models suggest that the disorder is the result of disruptions in brain development that occur during critical periods of neurodevelopment, such as prenatal exposure to maternal infection, malnutrition, or stress, and during adolescence when the brain undergoes significant changes. These disruptions can result in abnormal brain structure and function, leading to the development of schizophrenia. Additionally, genetic and environmental factors are thought to interact to increase the risk of developing the disorder. While there is still much to be learned about the underlying causes of schizophrenia, these neurodevelopmental models have greatly advanced our understanding of the disorder and provided a framework for the development of new treatments.

The neurodevelopmental models for schizophrenia are theoretical frameworks that attempt to explain the underlying causes of the disorder. Some of the key neurodevelopmental models for schizophrenia include:

Model:	Summary:
Prenatal exposure model	This model suggests that prenatal exposure to environmental insults, such as maternal infection, malnutrition, or stress, can disrupt brain development and increase the risk of developing schizophrenia.
Adolescent brain maturation model	This model suggests that abnormal brain maturation during adolescence, a critical period of brain development, can increase the risk of developing schizophrenia.
Neuroinflammation model	This model suggests that chronic low-grade inflammation in the brain, either due to environmental insults or genetic predisposition, can disrupt brain development and increase the risk of developing schizophrenia.
Synaptic pruning model	This model suggests that excessive synaptic pruning, or the elimination of unused synaptic connections in the brain, during adolescence can increase the risk of developing schizophrenia.
Genetic susceptibility model	This model suggests that genetic mutations or variations can increase the risk of developing schizophrenia by disrupting normal brain development and function.

These models are not mutually exclusive and multiple models may contribute to the development of schizophrenia in an individual. However, despite advances in our understanding of the underlying causes of schizophrenia, much more research is needed to fully understand the complex interplay of genetic, environmental, and developmental factors that contribute to the disorder.

Autism Spectrum Disorder:

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive behaviours. There is currently no cure for autism, and the underlying causes are still not fully understood. However, there are several neurodevelopmental models that have been proposed to help explain the development of autism and guide research and treatment efforts (Ozonoff, 1999).

Model:	Summary:
Social motivation theory	This theory proposes that autism arises from a fundamental deficit in the ability to engage in social interactions and understand the intentions and emotions of others.
Abnormal cerebellar development	This theory suggests that the cerebellum, which plays a role in motor coordination and cognitive processes, may be abnormally developed in individuals with autism, leading to deficits in social cognition and communication.
Excitatory/inhibitory imbalances	This theory proposes that autism results from imbalances between excitatory and inhibitory neurotransmitters in the brain, leading to abnormal brain activity and impairments in social interaction and communication.
Genes and environment interaction	This theory suggests that autism is the result of a complex interaction between genetic and environmental factors, such as exposure to toxins or prenatal stress.
Brain overgrowth	This theory suggests that early brain overgrowth in individuals with autism may contribute to the development of social and communication impairments.
Developmental theories	This theory suggests that autism may result from a series of abnormal developmental processes in brain development, such as synapse formation, myelination, and the emergence of neural circuits.

These neurodevelopmental models provide different perspectives on the development of autism and have helped to guide research and treatment efforts. However, the exact causes of autism are still not fully understood, and further research is needed to identify the underlying biological mechanisms and develop effective treatments for autism (Lai, 2014).

Narcolepsy:

Narcolepsy is a neurodevelopmental disorder characterized by excessive daytime sleepiness and disturbed nighttime sleep. It has long been recognized as a model for the study of sleep and wakefulness regulation, as it provides valuable insights into the neural mechanisms underlying these processes.

One of the key features of narcolepsy is the loss of hypocretin-producing neurons, which are responsible for regulating wakefulness and arousal. Hypocretin, also known as orexin, is a neurotransmitter that is produced by a small number of neurons in the lateral hypothalamus. There are two types of hypocretin: hypocretin 1 (HCRT1) and hypocretin 2 (HCRT2). These two peptides play a critical role in the regulation of sleep and wakefulness, and they act on specific receptors in the brain to promote wakefulness and inhibit sleep.

In individuals with narcolepsy, the loss of hypocretin-producing neurons leads to a reduction in wakefulness and an increase in daytime sleepiness, providing evidence for the critical role of the orexin system in the regulation of sleep and wakefulness. This has led to the development of new treatments for narcolepsy that target the hypocretin system, such as the use of wake-promoting drugs that increase the release of hypocretin.

Overall, narcolepsy serves as an important neurodevelopmental model for the study of sleep and wakefulness regulation, and it provides valuable insights into the neural mechanisms underlying these processes and the development of new treatments for sleep-related disorders.

Other neurodevelopmental models:

Model:	Summary
Radial arm maze	The radial arm maze was designed by Olton and Samuelson in 1976 to measure spatial learning and memory in rats. The radial arm maze is a behavioural test used to assess spatial memory and learning in rodents, such as rats and mice. In this test, the animal is placed at the centre of a radial maze with multiple arms, and it is required to navigate to the end of each arm to obtain a food reward. The number of errors made by the animal and the time taken to complete the task is used to evaluate its spatial memory and learning abilities.
Morris water navigation task	The Morris water navigation task is a behavioural test used to assess spatial learning and memory in rodents, such as rats and mice. In this test, the animal is placed in a pool of water with a hidden platform and is required to locate the platform by using visual cues in the environment. The time taken to locate the platform is used to evaluate the animal’s spatial learning and memory abilities.
T-maze test	The T-maze test is a behavioural test used to assess decision-making and cognitive flexibility in rodents, such as rats and mice. In this test, the animal is placed at the end of a T-shaped maze and is presented with two choices, one leading to a food reward and the other leading to a dead end. The animal’s choice of the arm to enter and the number of errors made in switching arms are used to evaluate its decision-making and cognitive flexibility abilities.
Hippocampal lesions	Richard G. Morris in 1981 showed that hippocampal lesions impaired spatial learning.
Latent inhibition test	The latent inhibition test is a behavioural test used to assess the role of attention and memory in the formation of associations. In this test, an animal is first exposed to a neutral stimulus, such as a tone, over a period of time, before being paired with a positive or negative event, such as a shock or food reward. The animal’s response to the previously neutral stimulus after pairing is then evaluated to determine the effect of prior exposure on the formation of associations. A reduction in responding to the previously neutral stimulus is considered evidence of latent inhibition, indicating that prior exposure has interfered with the formation of associations.
Light/dark box test	The light/dark box test is a behavioural test used to assess anxiety-like behaviour in rodents. In this test, an animal is placed in a box with two compartments, one brightly lit and the other dark, and its behaviour and the time spent in each compartment are observed and recorded. The animal’s preference for the dark compartment is considered an indicator of anxiety-like behaviour, as the dark compartment provides a safe, sheltered environment for the animal.
Elevated plus maze	The elevated plus maze is a behavioural test used to assess anxiety-like behaviour in rodents. In this test, an animal is placed in a maze consisting of four arms, two enclosed and two open, elevated off the ground, and its behaviour and the time spent in each arm are observed and recorded. The animal’s preference for the enclosed arms over the open arms is considered an indicator of anxiety-like behaviour, as the enclosed arms provide a safe, sheltered environment for the animal.

References:

(1) Lai, M. C., Lombardo, M. V., Chakrabarti, B., & Baron-Cohen, S. (2014). Subgrouping the autism “spectrum”: Reflections on DSM-5. PLoS biology, 12(4), e1001817.

(2) Nestler, E.J., Barrot, M., DiLeone, R.J., Eisch, A.J., Gold, S.J. and Monteggia, L.M. (2002). Neurobiology of Depression. Neuron, [online] 34(1), pp.13–25. doi:10.1016/s0896-6273(02)00653-0.

(3) Ozonoff, S., & Jensen, J. (1999). Brief report: specific executive function profiles in three neurodevelopmental disorders. Journal of autism and developmental disorders, 29(4), 171-177.