Neurotransmission of the Reticular System

The Reticular System is a set of connected nuclei in the brain that is responsible for regulating sleep-wake transitions and arousal. It contains the Reticular formation as its strongest component, which is responsible for regulating sleep cycle (and is one of the phylogenetically oldest parts of the brain).

Major Categories of Neurotransmitters

There are many substances known/suspected to be neurotransmitters, but we'll look at:

  • Monoaminse: Dopamine, Norepinephrene, Serotonin
  • Acetylcholine
  • Neuropeptides: Endorphins
  • Amino Acids: GABA, Glutamine

Dopamine

Dopamine is a monoamine neurotransmitter (meaning it contains an amino group connected to an aromatic ring by a two-carbon chain). It is important in reward-driven learning, and reduced levels play a role in diseases such as Parkinsons.

The major dopamine pathways are:

  • The Nigrostriatal – cell bodies in the SNPC in the midbrain project to the striatum
    • Loss of dopamine neurons here is a key neural marker for Parkinson’s disease
  • Mesolimbic - Ventral tegmental area (VTA) to the nucleus accumbens
    • Key for reward-learning
  • Mesocortical – Ventral tegmental area (VTA) to the cortex
    • Negative symptoms of schizophrenia, flat affect, loss of motivation

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Olds and Milner's 1953 Rat Stimulation

Olds and Milner noticed in 1953 that rats would associate stimulation of the medial forebrain bundle positively; choosing to return to places where that had happened, or to press levers to repeat it. This was instrumental for behavioural conditioning.

Electrical Stimulation and Reward Centres

Implanting electrodes into various areas (the medial forebrain bundle being the most expansive) and measuring/monitoring the stimulated dopamine release allows us to determine the proximity of the electrode to brain reward sites.

Agonist vs Antagonist Drugs

Agonists are chemicals that bind to receptor cells and trigger a response. This is in contrast to antagonists, who block the receptor cell and act as neutrals stopping any effect from occuring, and inverse agonists, who bind to the receptors and have the opposite effect to the agonist.

When a chemical acts as agonist on a receptor, it means that it is fulfilling the role of the other naturally produced (endrogenous) in transmitting the signal and having the desired effect, leaving the neurotransmitter to become a neuromodulator, thereby boosting the overall effect. However this does cause autoreceptors to throttle the production of whatever the natural agonist for the receptor is, leading to a deficiency until the sensitivity of the autoreceptors is diminished.

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Role of the Mesolimbic Pathway

Roy Wise in 1996 concluded that the reward for electrical self-stimulation was mediated by the Mesolimbic dopamine system.
This is supported by

  • how dopamine agonists and antagonists have the same effect when naturally occurring or just injected straight into the mesolimbic dopamine system
  • microdialysis showing dopamine release in the nucleus accumbens
  • his work looking at threshold levels for electrical self-stimulation (i.e. just directly stimulating a reward area, hence the 'self'); they alter when exposed to known dopamine agonists (e.g. amphetamine) and antagonists (pimozide)

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Prediction Error

Single cell electrophysiology has shown that the mesolimbic dopamine pathway encodes prediction error; output increases given an unexpected reward, and decreases when a reward is expected and none is given. It stays constant given an expected reward. (It signals how our expectations compare to reality).

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Serotonin

(Main article - serotonin)
Serotonin (also known as 5-HT) is also a monoamine neurotransmitter. It's thought to contribute to feelings of happiness and wellbeing.

Noradrenaline

Noradrenaline (also known as norepinephrine) is a catecholamine (has a catechol and a side-chain amine), that acts as both a hormone and a neurotransmitter. Noradrenaline is responsible for fight or flight, so things like heart rate and redirecting blood flow.

The CNS cells bodies for it are mainly located within the locos coeruleus (within the pons), and (like serotonin) has a distributed neuromodulatory role on total brain function.

Attention

The locus coeruleus noradrenaline system is thought to play two roles in attention;

  1. Baseline LC activation correlates to alertness. Sleep can be induced by reducing the function of the LC noadrenalin neurons, and firing rate within the LC correlates with drowsiness. We can map pupil dilation to LC levels, as below:
  2. Phasic LC Activation relates to attention to goal-relevant stimuli. E.g. the 'oddball paradigm' measures firing rate when an unexpected stimuli is produced (leading to a dramatic increase).

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Aston-Jones (2005) integrated the two attentional functions of LC noradrenaline neurons into a model of attention; too low LC levels leads to drowsiness, too high leads to distractibility. This resembles the classical Yerkes-Dodson relationship between arousal and performance.

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Acetylcholine

Acetylcholine is a polyatomic ion (covalently bonded, or two metal-bonded ions) that acts as a cholinergic neurotransmitter in the PNS and CNS. Acetylcholine (and other cholinergic neuron cell bodies) is located in the Nucleus Basalis and the pedunculopontine nucleus (atop the pons) - once again, it has a neuromodulatory role.

Other cholinergic neurons are shown below:

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Muscarinic Receptors (PNS)

Within the PNS acetylcholine acts upon Muscarinic receptors within the neuromuscular junction to transduce action potentials from neurons to control muscular activity in the SoNS and ANS.

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Nicotinic Receptors (CNS)

Within the CNS acetylcholine acts upon nicotinic receptors (where nicotine acts) to transduce action potentials to target neurons. Nicotine is linked to dopamine (reward) and to being a cognitive enhancer (reducing reaction times). However chronic exposure results in desensitisation of the nicotinic receptors, and hence cognitive impairment.

Alzheimer's

Alzheimer's used to be thought to be caused by acetylcholine degeneration, but due to the lack of impact of its use in cures and preventatives that theory has fallen out of mainstream popularity. AD is now thought to be caused by accumulation of protein deposits called plaques and tangles within neurons across the brain as a whole, as a result of dysregulation of normal cellular machinery.

Signal to Noise Ratio

Cells have a background firing rate, and tend to increase the frequency of their firing rate as a response to appropriate stimulation. Acetylcholine arguably increases the tuning of cellular activity to appropriate sensory stimulation (and decreases it without it) and thus increases the selectivity of behavioural and psychological functionality globally.

Sillito and Kemp (1983) showed the firing rates for visual cortical neurons in cats when exposed to (optimally oriented) bars of light across the visual fields, with and without acetylcholine.

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Sleep

The pedunculopontine cholinergic neurons play a role in sleep-wake behaviour; Arnulf et al (2010) found that stimulating the area in Parkinson's patients produced either wakefullness, sleep or dreaming depending on the frequency (low, high and sudden stops, respectively).

Endorphins

Endorphins are endogenous opioid (that's their receptor) peptide (polymers of amino acid monomers linked by peptide bonds) neurotransmitters. They're involved in blocking pain sensations and in subjective pleasure.

People often use the terms endorphins and opioids interchangeably.

Endorphins are located:

  • Within the ANS released from the pituitary to inhibit pain signalling broadly across the body.
  • In the SoNS where they inhibit sensory pain signaling.
  • Within other brain centres mediating subjective pleasure (euphoria).

Pain

Within the SoNS pain fibres (C and A Delta) from the skin/muscles/etc transmit sensory pain signals through the dorsal horn of the spine up and through to the somatosensory cortex. Transmission of pain and having a pain-detection system (enabling us to modify voluntary behaviour to avoid it) is important, but chronic pain can be debilitating rather than useful, and hence the endorphin system can be argued to have evolved to balance the pain transduction system out.

Within the ANS, endorphins are produced in the hypothalamus and released by the pituitary alongside ACTH (fight or flight stress hormone), to act as an analgesic (painkiller) alongside the stress response.

These endorphins diffuse through the blood and bind to presynaptic opioid autoreceptors. Opioid neurons that employ endorphins as a neurotransmitter are also present within the thalamus, brain stem, and spine. They inhibit pain in one of two ways:

  1. Axodendritic opioid neurons open K+ to hyperpolarize the membrane and decrease action potentials within the receiving cell
  2. Axoaxonic opioid neurons close Na+ (sodium) channels thus blocking neurotransmitter release in the receiving cells.

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Pleasure

When opioids are injected into the nucleus accumbens (part of the mesolimbic dopamine reward learning circuit), pleasant facial reaction to sweetness is increased.

Various parts of the nucleus accumbens increase our experience of pleasure, others increase our desire for pleasing things (e.g. increase how often a lever is pressed for a reward), suggesting that reward learning has an unconscious component.

Glutamate

Glutamate is the most abundant neurotransmitter in the brain, in over 50% of nervous tissue. It's important for learning and memory (neuroplasticity - change in strength of synaptic connections between neurons - i.e. behaviour change upon experience).

There are two functions performed by glutamate receptors:

  • AMPA and Kainate receptors respond to glutamate release by opening Na+ channels thus initiating an action potential within the receiving cell.
  • NMDA receptors respond to glutamate by opening calcium (Ca2+) channels and hence activating a change in the number of AMPA receptors and thus modifying the strength of the synaptic connection.

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Long Term Potentiation (Learning)

Long term potentiation is a long-lasting improvement in signal transmission between two parts of the brain by simultaneously stimulating them and creating a stronger synaptic communication between the two.

The improvement is shown by sending a week pulse from one electrode to the other, and noting the low detection, then stimulating both before resending the signal and noting the improved response.

The simultaneous stimulation activates NMDA receptors, hence increasing AMPA receptors and hence giving a better signal transmission.

Since the effect can last a long time it is considered to be the biological basis of learning. LTP confirms Hebbian learning: ‘Cells that fire together, wire together", which in turn explains Pavlovian Condition

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Strength of Glutamate Synaptic Connection

We can study how the strength of glutamate synaptic connections affects learning by looking at the injection of glutamate antagonists into systems that have been classically (pavlov) conditioned.

An example of this is Kandal's work with the Aplysia (sea snail) - it can be conditioned to withdraw it's gills with a siphon tap by conditioning it with tail shocks paired with siphon taps. However injecting glutamate antagonists into the abdominal ganglion blocks the learning.

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GABA

GABA is linked to inhibition, and one theory is that it forms a negative feedback loop with excitatory cells (e.g. glutamate, noadrenaline, dopaine, 5-HT, acetycholine).

Renshaw Cells

These loops (Renshaw cells) receive excitatory signals (to enable them to monitor activity) and send inhibitory signals (at a proportional level), and thus the output site of the action is capped at a certain optimum.

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Reciprocal Inhibition

Reciprocal Inhibition involves circuits whereby one pathway is led to dominate over closely connected pathways - inhibitory signals are sent to the other pathways whenever excitatory signals are detected, meaning that whichever has the most excitatory signals will when.

This means that only a restricted set of environmental stimuli are selected for attention, only a limited set of thoughts are evoked, and only a limited set of motor responses are performed.

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Epilepsy and Convulsant Drugs

The inhibitory affects of GABA are shown in conditions characterised by a lack of them; things such as epilepsy highlight what a lack of inhibitory mechanisms can lead to (seizures).

Anticonvulsant drugs target three main neural mechanisms:

  • Increase GABA availability
  • Block voltage-gated NA+ channels to reduce action potentials
  • Reduce the action of glutamate

Benzodiazepines were discovered accidentally in 1955 and have formed a class of psychoactive medication used to produce a sedative, hypnotic, anti-anxiety anticonvulsant, and muscle relaxant effect. They enhance the effect of GABA, thus increasing overall inhibition in the brain.

Gaba Receptor Subunits

The GABA receptor can be split into three components; alpha, beta and gamma. Different substances affect different components, which accounts for their different behavioural affects.

For instance alcohol affects the alpha, and Benzodiazepines affect the beta and gamma.

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