Motivation and emotion/Book/2023/GABA, motivation, and emotion

Overview
Case study

Samuel, a 32-year-old male, was diagnosed with schizophrenia at the age of 25. He displayed symptoms of psychosis, including hallucinations, delusions, disorganized thinking, and impaired social and occupational functioning. In Samuel's case, his altered mPFC GABA signaling had contributed to abnormal aversive learning processes, influencing his response to fear-inducing stimuli and potentially exacerbating his psychotic symptoms.



Gamma-aminobutyric acid (GABA) is a crucial component of the brain's inhibitory neurotransmitters system, maintaining balance between excitation and inhibition in neural circuits. GABA plays a significant role in regulating anxiety, stress, fear, and has implications in medical conditions like anxiety, autism, and Parkinson's disease. Dysregulation of GABAergic transmission can lead to neurological and psychiatric disorders.

GABA's role in emotion and motivation is explored, emphasizing its impact on neural circuits influencing sensory perception, cognitive functions, and emotional responses. Dysfunctions in cortical GABAergic transmission (Figure 1) affect cognitive, mood, and learning functions. GABA interneurons are vital for assembling cerebral cortex microcircuitry.

Ongoing research aims to unravel GABAergic networks and understand its dual inhibitory-excitatory nature. Emerging therapeutic avenues suggest GABAergic pathways as potential targets for emotional and motivational disorders. Overall, GABA emerges as a central player in understanding emotion, motivation, and related disorders.


 * Focus questions:Magnifying-glass.svg


 * 1) What is the biological and theoretical relationship between GABA and emotional regulation, including anxiety, stress, and fear?
 * 2) How do impairments in cortical GABAergic transmission influence cognitive, mood, learning, and behavior functions?
 * 3) How are ongoing research efforts exploring the intricate neural networks involving GABA - what are the future applications?

Introduction to GABA
Gamma-aminobutyric acid (GABA) stands out as an essential component in this complex system. GABA is the principal inhibitory neurotransmitter in the brain, shaping the balance between excitation and inhibition in neural circuits (see Figure 2) (Tadi & de Leon, 2023). This chapter highlights the significance of GABAergic neurotransmission in understanding the mechanisms underlying emotion and motivation, highlighting its vital role in maintaining cognitive and emotional equilibrium

Its primary role is to counteract the excitatory signals transmitted by neurotransmitters like glutamate. By binding to GABA receptors on postsynaptic neurons, GABA inhibits their activity, thereby reducing the likelihood of these neurons firing (Sharma et al., 2023). This inhibitory action has far-reaching effects on neural circuits, influencing processes ranging from sensory perception to cognitive functions and emotional responses. Antidepressant effects are associated with mechanisms restoring GABAergic inhibition (Luscher & Fuchs, 2015).

Neurotransmission and brain functions


Neurotransmission is the backbone of communication between neurons and is essential for various brain functions. The balance between inhibitory and excitatory signals is critical for the brain's proper functioning (Tadi & de Leon, 2023). Dysregulation of this balance can lead to a plethora of neurological and psychiatric disorders. Emotion and motivation, integral components of human behaviour, are intricately tied to neurotransmission patterns and the prevalence of psychiatric disorders. Understanding the role of neurotransmitters like GABA in these processes offers insights into the neural basis of emotions and motivations. Impairments in cortical GABAergic transmission influence cognitive, mood, learning, and behaviour functions (Ghosal et al., 2017). GABA interneurons are crucial for the creation of cerebral cortex microcircuitry and conducting brain function from development to adulthood (Ghosal et al., 2017).


 * Learning Box | Study | Gautheir & Nuss, 2015

Gautheir & Nuss, 2015 found that anxiety disorders arise from a dysfunction in the modulation of brain circuits that regulate the emotional response to potentially threatening stimuli. From a neurophysiological perspective, this highligts the role neural circuits have in anxiety comprise  inhibitory networks of principally GABAergic interneurons (Gauthier & Nuss, 2015).

Role of GABA in emotional processing
GABA reduces a nerve cell's ability to send and receive chemical messages throughout the central nervous system, therefore produces a calming effect. It plays a major role in controlling anxiety, stress, and fear. Fluctuating levels of GABA are linked to medical conditions including anxiety, autism, and Parkinson's disease (Pugle, 2022).

Emotion regulation and GABA
GABA enables the brain to slow down the central nervous system and regulates mood. Therefore alleviating extreme emotions such as stress, depression, and anxiety (Cuncic, 2022). It was found that reducing PFC GABA transmission through pharmacological methods resulted in impaired aversive conditioning, hindered retrieval of latent inhibition (LI), and intensified fear learning for a single stimulus (Piantadosi & Floresco, 2014). In relation to Pavlovian fear conditioning theory, mPFC GABA transmission aids in the designation of how Pavlovian fear memories are encoded, either mitigating the relative strength of a fear memory to a single CS or allocating fear or safety associations to different stimuli that may or may not be associated with aversive events. The GABAergic system in the PFC (Figure 3) is highly sensitive to stress and it plays a crucial role in the development of mood and cognitive disorders (Ghosal et al., 2017). Antidepressant drug effects depend on mechanisms that restore GABAergic inhibition. This enhancement of GABA function and show therapeutic efficacy in conditions such as MDD (Luscher & Fuchs, 2015).

GABA and emotional disorders: anxiety disorders.


GABA plays a significant role in the regulation of anxiety, in fact GABA's neurotransmitter system is the target for benzodiazepines and related drugs utilised to treat anxiety disorders (ICA Health, 2020). GABAergic inhibitory networks, GABAA receptor allosteric sites, neurosteroids, and the interplay between amygdala and prefrontal cortex play significant roles in shaping anxiety-related responses. This understanding opens avenues for targeted interventions aimed at modulating anxiety responses by influencing GABAergic transmission and receptor activity (Gauthier & Nuss, 2015). Drug-induced enhancement of GABA transmission (benzodiazepines, tiagabine, neurosteroids) has been found to have an anxiolytic effect (Argyropoulos et al., 2000). In summary, GABA plays a significant role in alleviating anxiety symptoms and in overall emotional regulation.

1. Reduced Brain-derived neurotrophic factor (BDNF) function found in hippocampus linked to GABAergic neuroplasticity dysfunction (GND) and anxiety in aged mice.
 * Learning box | Mice & anxiety study (Zhu et al., 2019)

2. Chronic exogenous BDNF treatment improved behavior, cognitive function, and neuroplasticity.

3. Aged mice showed decreased BDNF mRNA, protein, GABA levels, GABAA-R α2 and α5 subunits, and GABA+ neurons, linked to anxiety-like behavior.

Schizophrenia
Research has found correlations regarding GABAergic transmissions and the prevalence and symptoms of mood disorders such as schizophrenia. Changes in emotional learning parallel observations in schizophrenic patients suggests that dysfunction in PFC (Figure 4) GABA circuits could contribute to abnormal affect regulation seen in disorders like schizophrenia. The findings propose that treatments aimed at normalising PFC GABA activity might be beneficial in mitigating emotional abnormalities associated with the disorder (Piantadosi & Floresco, 2014).

Major Depressive Disorder (MDD)
Additionally, research has found correlations between GABA and major depressive disorder. Reduced GABAergic inhibition in cortex, hippocampus, and ventral pallidum nucleus (VPN) results in cellular, hormonal, and behavioural MDD modifications (Luscher & Fuchs, 2015).

Premenstrual Dysphoric Disorder (PMDD)
Similiarily, in relation PMDD greater cerebellar gray matter volume and metabolism have been observed in PMDD along with altered serotonergic and GABAergic neurotransmission. In addition, enhanced amygdala and diminished fronto-cortical activation have been found in response to emotional stimuli (Dubol et al., 2020). Therefore, GABA is a significant factor in the longterm symptoms of mood disorders including schizophrenia, MDD, and PMDD and it is highly recommended it be researched further for future implications.

GABA and motivation: the neural mechanisms underlying motivation
Neural mechanisms such as transmitters and neuromodulators regulate effort-related choice and motivation, including acetylcholine, adenosine, serotonin and GABA (Le Heron, C. et al 2019) GABA relies on dopamine systems for which play crucial roles in regulating behavioural activation, effort exertion, and decision-making. Interference with dopamine transmission leads to low-effort choices without affecting primary reinforcing effects. Effort-related functions involve a neural circuitry with multiple neurotransmitters in basal ganglia, limbic, and cortical areas (Salamone et al., 2016)

Classical motivation theory asserts there are distinct levels of motivation. Therefore behaviour can be directed towards some stimuli (e.g., food) and away from others (e.g., stressors). Motivation has an activation or energetic component meaning motivated behaviour is characterised by a high degree of behavioural activation e.g. speed, vigour or persistence in responses (Salamone et al., 2016). Depression, schizophrenia, and Parkinson's demonstrated a reduced high effort selection and motivation, however autism presents the opposite.(Salamone et al., 2016)Additionally, depression, schizophrenia and Parkinson’s disease are distinct disorders with unique sets of behavioural and neural pathologies, however there may be overlap in terms of the neural mechanisms involved in the motivational dysfunctions that have been observed (Salamone et al., 2016).

FUN FACT (Salamone et al., 2016)

Brain regions involved in behavioral activation and effort-related processes are similar in rodents and humans.

Reward pathways and GABA


Reward pathways of the brain are connected to the ventral tegmental area (VTA) which releases dopamine in turn releasing feelings of pleasure. VTA GABA neuron's physically activate reward predictive cues, and are also strongly modulated by drugs of abuse and stress, pointing towards potential roles in substance use and stress-related neuropsychiatric disorders. The VTA is a hub of the mesocorticolimbic circuitry that plays a significant role as a mediator in reward, motivation, cognition, and aversion (Bouarab et al., 2019). Optogenetic stimulation of VTA GABA neurons can directly suppress the activity and excitability of neighbouring DA neurons, demonstrating the dynamic interplay between VTA DA and GABA neurons and how they control the initiation and termination of reward-related behaviours (van Zessen et al., 2012). Rats with ventral pallidum GABAergic inactivation demonstrated diminished willingness to work hard on an instrumental task to obtain sucrose reward, and instead shift their choice toward an average meal that could be gained more easily for less effort (Farrar et al., 2008).

Future directions and applications of GABA research
GABA is a fascinating and crucial component of emotional and motivational regulation, therefore contributing current research findings to future applications and studies is vital to understand GABAergic transmission and therapeutic treatments. Zorumski et al., 2013 investigated neurosteroids as a therapeutic opportunity treatment for stress and depression. their emphasis was on steroid derivatives that alter the function of the γ-aminobutyric acid (GABA) transmitter system, as they discovered (Bouarab et al., 2019) noted the complexity of VTA microcircuit and the importance for understanding how VTA GABA neurons regulate reward, aversion, motivation, and affect in health and disease. Research into specific roles of subpopulations within the VTA microcircuit and their impact on distal circuits is crucial for future applications regarding reward process theory, emotional and motivational regulation. Sikes-Keilp & Rubinow, 2023 highlighted insights into the etiopathogenesis of affective disorders, considering that: symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics.

Additionally, further research in GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signalling in the brain. In relation to emotions such as fear, (Piantadosi & Floresco, 2014) found reducing PFC GABA transmission results in impaired aversive conditioning, hindered retrieval of latent inhibition (LI), and intensified fear learning. However, further research in neural mechanisms underlying the expression and recall of learned irrelevance may shed additional light on disinhibition of the mPFC and how it may disrupt the appropriate recall of CS associations in future applications.Further research surrounding the biological functions of the limbic system would assist in understand the nature, extent and prevalence of anxiety disorders. Gauthier & Nuss, 2015 study found the medial PFC and amygdala to be hypoactive in PTSD and generalised anxiety disorder.

Conclusion
The vital role of GABA in the brain's complex neurotransmission system cannot be overstated. As the principal inhibitory neurotransmitter, GABA maintains the delicate equilibrium between neural excitation and inhibition, a balance critical for proper brain function. This chapter has illuminated GABA's multifaceted involvement in emotion, motivation, and related disorders, painting a comprehensive picture of its influence. Most importantly, dysregulation of GABAergic transmission underpins a range of neurological and psychiatric disorders, emphasising the pivotal role it plays in maintaining mental well-being.

The chapter delves into the complex interplay between GABA and emotional disorders, including anxiety, schizophrenia, major depressive disorder, and premenstrual dysphoric disorder. GABA's biological factors and its involvement in neural circuits provides vital governance of these conditions and sheds light on its potential as a therapeutic target for intervention and therapeutic avenues such as neurosteroids as a therapeutic opportunity treatment for stress and depression. Furthermore, the exploration of GABA's role in motivational states unveils its interactions with other neuromodulators and neurotransmitters, offering insights into the intricate neural mechanisms that drive behaviour, decision-making, and effort-related choices. GABA's inhibitory nature has biological influences and processes ranging from sensory perception to cognitive functions and emotional responses, therefore maintaining cognitive and emotional equilibrium.