Paper 1 - Biological Approach - The Value of Animal Research (HL)

Advantages of using animal models

- Animals may be used in cases where it would be unethical to use human subjects.

- Animal studies allow researchers to embrace the full lifespan. While human subjects often outlive researchers themselves, laboratory mice live 2-3 years and this presents an opportunity to see their behavior across their lifespan and even across generations.

- Animal research may be highly controlled. For example, the knockout technique has been used to selectively switch off one of the genes in the DNA sequence. All other things being equal, this technique provides great insight into the function of individual genes. The ability to better control confounding variables means higher internal validity of the experiments.

Disadvantages of using animal models

- Although we share DNA with animals, the anatomic, metabolic, and cellular differences between animals and people make animals poor models for human beings. Animals and humans are never exactly the same, and we can never know the extent of the difference. This means that animal research, if successful, still needs to be replicated with humans in order to be sure that findings are generalizable.

- Many key symptoms of some disorders cannot be modeled in lab animals. For example, in depression we cannot model depressed mood, feeling of worthlessness, and recurring thoughts of death or suicide. However, we can model learned helplessness, chronic mild stress, and social withdrawal.

- Animals are tested in strictly controlled laboratory environments, so arguably they may be under stress. As a result, their reactions to experimental manipulations may not be quite the same as in their natural environments: there may be an issue with ecological validity.

Argument that animal research does provide insight into human behavior

- Animal studies allow researchers to manipulate and control environmental variables more effectively than in human studies. This level of control minimizes confounding variables and helps establish clear cause and effect relationships. For example, stressors, diets, and genetic backgrounds can be standardized in human studies.

- Mice are about 97% the same as humans genetically, and chimpanzees a little less than that. Therefore, they seem prime examples of animal models for research. Genetic research often analyzes simpler systems in order to gradually develop an understanding of more complex ones, and it is in genetics that the usefulness of animal research for developing theories about human behavior and treatment for human disorders.

- Animal models have been pivotal in developing treatments for diseases like Parkinson's, Alzheimer's, and depression. For instance, dopamine research in rats and monkeys contributed to the development of L-DOPA, a treatment for Parkinson's disease.

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Human beings are animals and it is only via experimentation that insight into particular types of behaviour can be achieved, particularly at the biochemical level of experimentation

Using human beings as participants can only go so far, due to ethical restrictions placed on the use of humans in research: this is when the use of animals as subjects is useful

There are some perceived similarities between human brains and animal brains, particularly with higher-order animals such as chimpanzees, who share 98.8% of their DNA with humans therefore this has real value as a model of human behaviour

Some animal studies involve injecting animals with hormones, lesioning part of their brain or implementing genetic modification: all techniques that would be unethical to use on humans but which may provide scientific breakthroughs

Argument that animal research provides limited insight into human behavior

- There have been some examples of animal research that have been much less successful in giving us insight into human behavior. While the mouse is genetically almost identical to the human, it seems that investigating mouse disease responses has given little insight into human disorders. For example, certain genetic mouse models of Alzheimer's disease looked promising until scientists examined that animal's brains and found missing there the brain damage (amyloid plaques or neurofibrillary tangles) that characterizes the disease. Other models would have the neuronal damage, but not significant memory deficits. It may be that amyloid proteins are deposited over years, but only begin to have an effect when someone researches their seventh or eight decade, and mice only live for about 2 years (Sasaguri et al 2017). While those two years are seen as corresponding to the full human life span, this may not be the case. Therefore, animal studies lack external validity and cannot be generalized to humans.

- Evidence provided by the Guardian newspaper criticizes using mice for several reasons. For example, paracetamol and aspirin are both deadly to mice; thalidominde, prescribed for pregnant women in the late 1950s to alleviate morning sickness, resulting in many thousands of congenital malformations, despite having been successfully tested on mice; 95% of the drugs thought to be promising after experiments on mice fail when subjected to clinical trials.

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There are strong moral and ethical arguments for not using animals in research: causing distress to the animal; depriving the animal of their natural environment; destroying the animal for the sake of the research; using animals without considering possible alternative solutions; the assumption that an animal life is less valuable than a human life

Humans and animals share similarities but they are, clearly, not completely identical: humans are more sophisticated in terms of their cognitions, motivations and higher-order thinking than animals so the results of animal studies cannot be completely generalized to humans

Some research using animals has been prone to methodological flaws e.g. not using random allocation to conditions, not using a single‐blind design, baseline measurements being unreliable, testing the animals in the artificial environment of the lab, rather than in the wild

Manipulation of neurotransmitters in animals (neurotransmitters - brain and behavior)

Animal studies allow researchers to manipulate neurotransmitter levels in controlled ways, such as by inc levels, blocking receptors, or activating specific neural pathways. This allows researchers to isolate the effects of neurotransmitters, which they can't do in human studies due to ethical concerns.

Insight into neurological disorders

Studies using rodents have demonstrated the role of acetylcholine in spatial memory and cognitive functions. By blocking acetylcholine receptors with drugs like scopolamine, researchers have been able to simulate memory impairments, helping to understand conditions such as Alzheimer's disease and guiding the development of treatments aimed at improving memory deficits.

Relevance to human behavior

Although animal studies provide useful insights, applying the findings directly to humans may be tricky as the species differ. For example, the GABA system in rodents and humans works similarly but has differences in how many GABA neurons there are and how they function. These differences can change how GABA controls things like anxiety or motor skills, so results from animal studies may fully apply to humans without further testing.

Acetylcholine in Memory and Learning

ACh plays a vital role in memory and learning. In animal studies, researchers often manipulate ACh levels to examine its role in cognitive processes like spatial memory. For example, scopolamine, which blocks ACh receptors, is used in rodents to investigate memory impairments.

By injecting chemicals like scopolamine directly into specific brain regions (e.g. hippocampus), researchers isolate the effects of ACh on memory encoding and consolidation.

GABA's role in memory

Plays a significant role in memory as it regulates the activity of neural circuits involved in learning and memory by preventing overexcitation, which could impair memory consolidation and retrieval.

Studies in rodents have shown that reducing GABA activity (e.g. blocking GABA receptors) can lead to hyperactivity in neural circuits, which can disrupt the balance needed for processes like encoding and retrieval, causing memory impairments.

Roger and Kesner (2003) aim

To determine the role of acetylcholine in the formation of spatial memory

Roger and Kesner method

Sample of 30 rats which acclimatized to a Hebb Williams maze by placing food in one of the corners. Once the rats were familiar with the maze and were no longer afraid of their environment, the experiment began.

The rats were randomly allocated to one of two conditions. The rats were either injected with scopolamine or with a saline solution (placebo injection) into the hippocampus 10 minutes before running the maze. As both were injections, this ensured that getting an injection was not responsible for a change in memory, as injections can increase adrenaline which could be a confounding variable.

Encoding of memory was assessed by the avg number of errors made on the first five trials of day 1 compared to the last five trials of day 1, whereas the average number of errors made on the first 5 trials of day 2 compared to the last 5 trials of day 1 was used to assess retrieval.

Roger and Kesner results

The scopolamine group took longer and made more mistakes in the learning of the maze (there was a higher average number of mistakes made on the last 5 trials on day 1). However, it did not appear to have an affect on retrieval of memories that had already been creates. It appears acetylcholine has an important role in the consolidation of spatial memories.

Roger and Kesner conclusion

Roger and Kesner's study highlights the role of acetylcholine in memory. Rats injected with scopolamine, which blocks acetylcholine receptors, made more errors and took longer to learn a maze, demonstrating impaired memory consolidation. However, memory retrieval of previously learned tasks was unaffected. This suggests acetylcholine is essential for encoding and forming new spatial memories but is not necessary for retrieving already stored information.

This study demonstrates the value of animal models in understanding the role of neurotransmitters like acetylcholine in human memory processes, providing insights into the biological mechanisms underlying learning and memory.

Roger and Kesner evaluation

+ A strength of the study is its use of a rigorously controlled experimental design. Researchers implemented a placebo condition to compare the effects of scopolamine on memory consolidation. This ensured that any differences observed were due to the manipulation of acetylcholine levels, not external variables. This control of confounding variables increases the study's reliability and supports its internal validity. This strength emphasizes how the controlled experimental design in animal models provides insights into the role of neurotransmitters in memory, though caution is needed when generalizing the findings to more complex human memory processes.

- A further limitation is the artificial nature of the task used in the study. The maze-learning task does not fully replicate how memory is used in real-life situations. This reduces the ecological validity of the study, as the controlled setting may not reflect the complexity of memory processes in natural environments. Therefore, this highlights how animal models, while useful for controlled experiments, may not fully capture the complexity of human memory processes due to the artificial nature of tasks used in research.

Prevot aim

to investigate whether the manipulation of GABA levels could have a positive influence on impaired memory function in an animal model hypothesis -> using an agonist (an imidazobenzodiazepine) which activates the a5-GABA receptor site in the hippocampus would inc the inhibition of neural activity, improving memory function.

Prevot method

sample of mice that suffered memory impairment due to chronic stress, and older mice w/ memory impairment.

used a double-blind experiment with a pre-test/post-test design. the mice were either allocated to the placebo condition (control group) or the drug condition.

mice were placed alone in a y-shape maze to test their spatial working memory. mice w/ healthy working memory can alternate between the 2 arms of the 'y' when continually placed back to the start of the maze. mice that have impaired working memory are more likely to explore the same arm of the 'y' they had just explored.

Prevot results

the drug treatment group performed almost as well as the mice that had not been chronically stressed.

older mice treated w/ the drug showed significantly higher levels of performance on the task than those given the placebo.

after the study, the mice were sacrificed and the researchers found the mice w/ the drug treatment showed new hippocampal cell growth, reversing the effects of stress and ageing.

Prevot conclusion

GABA agonist led to an improved spatial working memory in mice w/ chronic stress and old age. This supports the theory of neurotransmitters as it shows how GABA is involved in memory formation.

This could be applied to human behavior as it demonstrates how neurotransmitters like GABA are involved in cognitive functions like memory formation.

Prevot evaluation

- the study uses an animal model. this means the result of this study can only be cautionally generalized to humans, despite the similarities in the role of GABA in memory in humans. Therefore, the drug will have to go through human testing to determine if the findings are generalizable to a human sample.

+ although the study is recent (2019), it is based on an established theory - there's a body of research that has similar results, based on the assumption of GABA's role in memory. For example, this study confirms some of the findings of Koh et al (2017). Therefore, there is other research that supports this study, increasing it's reliability.

Using animal models to study hormones and behavior: Glucocorticoids

Class of steroid hormones produced by the adrenal cortex that plays a crucial role in regulating metabolism, immune response, and the body's response to stress.

Cortisol is the primary glucocorticoid in humans, and is the central hormone in the hypothalamic-pituitary-adrenal (HPA) axis, regulating the stress response in both humans and animals.

Elevated cortisol levels in both humans and animals impair hippocampal function, which is crucial for long term and spatial memory. Chronic stress leading to high cortisol levels is associated with cognitive decline, including Alzheimer's disease in humans, mirroring findings from animal studies.

Research indicates cortisol can influence social behaviors (e.g. inc aggression or social withdrawal under stress). Animal studies provide parallels to how elevated cortisol levels affect human interactions, helping explain stress-induced changes in social functioning.

Animal studies manipulating cortisol levels help identify therapeutic targets for managing stress-related conditions in humans.

Adrenocorticotropic hormone (ACTH)

Released from the anterior pituitary and plays a role in HPA axis by stimulating the adrenal cortex to release glucocorticoids like cortisol (humans) or corticosterone (rodents).

In rodent models, ACTH and its regulation are studied to understand how the HPA axis adapts to chronic stress and resilience. For example, dysregulation in ACTH signaling can lead to heightened stress reactivity.

Studies have shown that ACTH indirectly influences behavior through its role in glucocorticoid release, impact learning, memory, and social behaviors.

Since the HPA axis is conserved across mammals, findings in animal research can help model human stress related disorders like depression.

By exploring the role of ACTH in animal models, researchers gain a better understanding of how stress and its regulation affect human behavior, offering valuable insights for mental health treatment and resilience strategies.

Meaney et al (1988) aim

To determine the effect of glucocorticoids (stress hormones) on memory.

Meaney et al method

Independent samples design. The rats were randomly allocated to one of two conditions.

Treatment group: Newborn rats were handled daily by the researchers for 3 weeks - from the day of their birth until the day of weaning. During this time they were taken away from their mothers and placed in a plastic container lined with a paper towel. They were then brushed for an intense 15 minutes to stimulate the grooming of the mother rat.

The rats in the control group were taken away from their mother but there was no handling by the researchers. This group served as the control condition.

To test the effect of these elevated rates of stress hormones over their lifetime, two year old rats were put into a pool of milky water. In the pool was a platform. Meaney and his team tracked the rout of the rats as they sought out the platform based on the rats' memories of previous attempts to escape the water.

Meaney results

High levels of glucocorticoids - stress hormones - in the early life of a rat resulted in changes that affected the rats in old age. Inc exposure to adrenal glucocorticoids accelerated hippocampal neuron loss and cognitive impairments in ageing.

Rats taken away from their mothers at a young age and were not groomed by the researchers took a more circuitous rout to get to the platform when they reached old age.

Hippocampal cell loss and pronounced spatial memory deficits emerged w/ age in the neglected rats but were almost absent in the rats groomed by the researchers.

Meaney conclusion

Long term exposure to cortisol causes neurons to admit more calcium through channels in their membrane, leading to overstimulation which then leads to hippocampal cell death. This creates a problem in the ability to create memory as the hippocampus is the location of acetylcholine receptor sites. Loss of hippocampal cells correlates with lower levels of acetylcholine. Research shows there is a correlation between high levels of glucocorticoids, low levels of acetylcholine, and Alzheimer's.

Meaney evaluation

+ A strength of the study is its use of a well-controlled experimental design. The researchers compared rats raised in different environments, controlling for variables like genetic differences. This allowed for a clear assessment of how environmental factors impact brain development and memory, ensuring that the results were due to the manipulation of the environment. This highlights how animal models, like rats, allow for controlled manipulation of environmental variables, offering clear insights into how such factors influence brain development.

- A limitation of the study is its use of animal models. The study was conducted on rats, and while they share some biological similarities with humans, their cognitive and emotional processes are not identical. This limits the generalizability of the findings to humans, as the brain and behavior of rats may not fully reflect human experiences. This limitation demonstrates how animal models, may not fully capture the complexity of human cognitive and emotional processes, limiting the generalizability of the findings.

Barr et al (2004) aim

To determine the effect on the adrenocorticotropic hormone (ACTH) and cortisol levels of infant monkeys of separation from their mother soon after birth and any interaction this may have with a variation on the serotonin transporter gene promoter (rh5-HTTLPR).

Barr method

208 infant monkeys from 7 birth cohorts. They were either reared with their mother (N=141) or in peer-only groups (N=67). At 6 months, the ACTH and cortisol levels were determined. Mother reared (MR) monkeys were reared for the first 6 months of life in social groups comprising their mother and 7-11 other females and two males. Peer-reared monkeys (PR) were separated from their mothers at birth and hand reared for 37 days.

For the first 13 days they were hand fed and kept in an incubator; from 15-37 they were placed alone in a nursery cage and provided a terry cloth covered rocking surrogate with a bottle fixed to it. At 37 days, they were placed in a cage w 3 other monkeys of the same age.

When they were abt 6 months old, they were subjected to 4 sequential four-day separations from their peers (PR) or family group (MR). Each was removed rom the home cage and placed in an isolation cage where they could hear but not see the others. Blood samples were taken before removal from the home cage, one hour after removal, two hours after removal, and on day 4 a blood sample and spinal tap were taken.

The rh5-HTTLPR genotype was identified from the blood samples, 153 had the long/long polymorphism and 55 had the short/long.

Barr results

There was a significant rise in ACTH after one hour in the acute stress condition, and a significant fall in ACTH after 4 days in the chronic stress condition. There were no significant direct effects of the rh5-HTTLPR genotype on ACTH levels, although during the acute phases of separation, PR monkeys with l/s genotype had higher ACTH level than did those with the l/l genotype.

Cortisol levels rose in response to separation stress, especially among the MR monkeys. There was an interaction between rearing, baseline cortisol levels and rh5-HTTLPR: PR l/s monkeys had lower baseline cortisol levels than the other groups. During chronic separation, PR monkeys had a lower cortisol level than MR monkeys.

Barr conclusion

This demonstrates that, although environmental factors can contribute to stress-related disease, genetic differences are also important, with the variation on the serotonin-transporter gene promoter being implicated in the rise in ACTH levels under acute stress. This research also implicated that the endocrine system, which variations in ACTH and cortisol level in response to an interaction between rearing style and the gene variation.

Barr evaluation

+ The study demonstrated the interaction between environment, genetic variation, and the endocrine system. It highlighted how early-life disadvantage (peer-reared monkeys) combined with the l/s genotype resulted in elevated ACTH levels during acute stress conditions. This finding provides insight into the complex gene-environment interactions that influence stress regulation and endocrine activation. By connecting early life experiences, genetic factors, and physiological responses, the study advances our understanding of developmental stress mechanisms.

- Ethical concerns associated with the study. Peer-reared monkeys were separated from their mothers at birth and subjected to isolation during stress tests, which likely caused significant distress. Although this design provided valuable data, the ethical implications of such procedures highlight concerns about the welfare of the monkeys. This raises important questions about the balance between scientific insights and animal welfare in psychological research.

Using animal models to study genes and behavior: mother-infant separation in macaques

Research shows that early separation from mothers significantly impacts stress hormone levels such as ACTH and cortisol, in infant macaques. These heightened levels of stress hormones can affect neurodevelopment and behavior, mirroring stress-related conditions in humans. Separation also interacts with genetic factors like the rh5-HTTLPR, which is critical in regulating serotonin, a neurotransmitter linked to mood regulation.

Role of the rh5-HTTLPR

Variations in this gene influence how macaques respond to stress. The 'short' allele of the gene is associated with heightened sensitivity to environmental stressors. For macaques with this allele, early life stress (e.g. maternal separation) exacerbates behavioral issues like anxiety and impaired social behavior. These findings parallel similar gene-environment interactions observed in humans.

Epigenetic regulation plays a role; early experiences can modify gene expression w/o altering the DNA sequence, potentially silencing or activating stress response pathways.

Epigenetics and stress response

Maternal care, or lack thereof, influences epigenetic markers in genes associated with stress regulation. For example, well-cared for macaques show more efficient regulation of cortisol, leading to better stress resilience and healthier development. This finding aligns with human studies, where early nurturing environments buffer against genetic predispositions to anxiety of depression.

Epigenetic research in rodents has provided significant insight into how maternal care impacts stress regulation and behavior. Studies demonstrate that variations in maternal care influence epigenetic markers in genes regulating the HPA axis, which governs the stress response.

Implications for human behavior

Studying genes in animal models like macaques provides crucial insights because of their genetic and physiological similarities to humans. The interplay of genetic predispositions (e.g rh5-HTTLPR variations) and environmental factors (e.g. maternal care) in macaques reflects similar processes in humans.

It highlights the potential for early interventions to mitigate the effects of adverse environments on mental health through epigenetic pathways.