Neuron firing

The human brain is comprised of many millions of interconnected units, known individually as biological neurons. Each neuron consists of a cell to which is attached several dendrites (inputs) and a single axon (output). The axon connects to many other neurons via connection points called synapses. A synapse produces a chemical reaction in response to an input. The biological neuron fires if the sum of the synaptic reactions is sufficiently large. The brain is a complex network of sensory and motor neurons that provide a human being with the capacity to remember, think, learn and reason. 

Now, to be sure, McCulloch-Pitts neurons are unrealistically rendered versions of the real thing. For example, the assumption that neuronal firing occurs synchronously throughout the net at well defined discrete points in time is simply wrong. The tacit assumption that the structure of a neural net (i.e. its connectivity, as defined by the set of synaptic weights) remains constant over time is known be false as well. Moreover, while the input-output relationship for real neurons is nonlinear, real neurons are not the simple threshold devices the McCulloch-Pitts model assumes them to be. In fact, the output of a real neuron depends on its weighted input in a nonlinear but continuous manner. Despite their conceptual drawbacks, however, McCulloch-Pitts neurons are nontrivial devices. McCulloch-Pitts were able to show that for a suitably chosen set of synaptic weights wij, a synchronous net of their model neurons is capable of universal computation. This means that, in principle, McCulloch-Pitts nets possess the same raw computational power as a conventional computer (see section 6.4). 

Primary generalized seizures are also heterogeneous with respect to their clinical features. Such seizures can impose as absence epilepsy, which is characterized by a brief interruption of consciousness due to highly synchronized neuronal activity involving thalamocortical networks without increases in neuronal firing rate. On the other hand, tonic-clonic convulsions with loss of consciousness are often also primarily generalized. 

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

Oscillations in the EEG of between 0.5 and 4 Hz, sometimes also called delta activity. SWA is a hallmark of the sleeping brain, and is most prevalent in the deepest sleep stages (stages 3 4). The slow oscillations arise from widespread synchrony of neuronal firing, particularly in the thalamocortical circuits. 

The LVA ai subunits are blocked by moderate to low (10 pM) concentrations of nickel and bind the channel blocker mibefradil and kurotoxin. Both compounds are not specific LVA channel blockers because they block also Cavl. x and Cav2.x channels at about tenfold higher concentration. Interestingly, the endogenous cannabinoid anandamide binds to LVA channels and stabilises the inactivated state. This effect decreases T-type calcium current and neuronal firing activities. 

Opioids bound to MOR on postsynaptic terminals promote the efflnx of potassinm (K ) via K+ channels. The net effect of active MOR receptor resnlts in hyperpolarization of the post-synapse causing inhibition of neuronal firing. Stndies have shown MOR effects at the pre- and post-synapse synergistically decreases the perception of pain (Glanm et al. 1994 Kohno et al. 1999 Williams et al. 2001 Yoshimnra and North 1983). 

In the CNS there are many forms of neuronal organisation. One neuron can have many synaptic inputs and a multiplicity of NTs and NT effects are utilised within a complex interrelationship of neurons. There are also positive and negative feedback circuits as well as presynaptic influences all designed to effect changes in excitability and frequency of neuronal firing, i.e. patterns of neuronal discharge. 

Figure 1.9 Comparison of the effects of an endogenously released and exogenously applied neurotransmitter on neuronal activity (identity of action). Recordings are made either of neuronal firing (extracellularly, A) or of membrane potential (intracellularly, B). The proposed transmitter is applied by iontophoresis, although in a brain slice preparation it can be added to the bathing medium. In this instance the applied neurotransmitter produces an inhibition, like that of nerve stimulation, as monitored by both recordings and both are affected similarly by the antagonist. The applied neurotransmitter thus behaves like and is probably identical to that released from the nerve...

A number of studies have shown that adenosine inhibits neuronal firing both in vitro and in vivo and is itself released during intense neuronal activity. It can protect against PTZ seizures in rodents while the antagonist theophylline is proconvulsant. No clear picture of its role in human epilepsy has emerged. 

It was found, however, that if neuroleptic administration was continued for two weeks then neuronal firing stopped. Also while the neurons could not be made to fire by the excitatory NT glutamate, the inhibitory NT GABA activated them by reducing the... 

Dyskinesias are thought to be due to increased DA function, which would not be an obvious effect of a DA antagonist but the early acute ones could reflect the increase in DA neuron firing and release produced by such drugs, in the manner described above, overcoming the postsynaptic DA receptor block achieved in the striatum. 

More importantly for this discussion is the finding that chronic administration of an antidepressant produces a similar increase in the concentration of extracellular 5-HT in the terminal field together with recovery of neuronal firing. Presumably this is because the prolonged elevation of extracellular 5-HT around the neurons in the Raphe causes progressive desensitisation of the somatodendritic 5-HTia receptors. At this point, inhibition of their firing does not occur and so more 5-HT is released in the cortex (see Hervas et al. 1999). 

A related strategy would be to inactivate the 5-HTib/id autoreceptors which are found on serotonergic nerve terminals and so prevent feedback inhibition of 5-HT release in the terminal field. These drugs would not prevent the impact of indirect activation of 5-HTia receptors, and the reduced neuronal firing, by SSRIs (described above), but they would augment 5-HT release in the terminal field once the presynaptic 5-HTia receptors have desensitised. Selective 5-HTib/id antagonists have been developed only recently but will doubtless soon be tested in humans. 

Opioids act in the brain and within the dorsal horn of the spinal cord, where their actions are better understood. The actions of opioids important for analgesia and their side-effects involve pre- and postsynaptic effects (1) reduced transmitter release from nerve terminals so that neurons are less excited by excitatory transmitters, and (2) direct inhibitions of neuronal firing so that the information flow from the neuron is reduced but also inhibitions of inhibitory neurons leading to disinhibition. This dual action of opioids can result in a total block of sensory inputs as they arrive in the spinal cord (Fig. 21.5). Thus any new drug would have to equal this dual action in controlling both transmitter release and neuronal firing. 

Although some studies show that noradrenaline inhibits neuronal firing it is generally considered to increase behavioural activity and arousal. This impression is borne out to the extent that CNS stimulants, like amphetamine, increase release of noradrenaline and produce behavioural and EEG arousal, while reserpine, which reduces noradrenaline storage and hence release, causes psychomotor retardation. It is also supported by... 

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