Framework for internal sensation of pleasure using constraints from disparate findings in nucleus accumbens

Table 1 Key findings in nucleus accumbens and constraints provided by them

Finding	Constraint
LTD can be induced at the spinous region of MSNs of NAc[17,18,28]	Energy applied at the spinous region leads to depression of potentials at the recording electrode placed at the postsynaptic region or on MSN soma
LTD induction has a time delay following stimulation[17,18] comparable to that of LTP induction[13,14]	A time-dependent cellular change is taking place during the delay period following LTD stimulation
Similar to LTP, LTD is also NMDA receptor-dependent[82]	LTD induction takes place through activation of NMDA receptors of glutamatergic synapses
When rewards or conditioned stimuli that predict reward are presented, dopamine neurons in the VTA increase their firing[91,92] releasing dopamine in their terminals that synapse with spines of MSNs in NAc	Dopamine produces certain changes at the spines of MSNs that synapse with excitatory inputs
Drugs of abuse such as cocaine increase dopamine levels in the NAc[28]	Dopamine has certain actions on the spines of MSNs that synapse with excitatory inputs
Dopamine attenuates postsynaptic potentials elicited by stimulation of different excitatory inputs to NAc shell region[40]	Action of dopamine on spines of MSNs that synapse with excitatory inputs attenuates postsynaptic potentials when these excitatory inputs are stimulated through a mechanism
Dopamine reduces excitability of MSNs in vitro[93]	Action of dopamine on the spines of MSNs that synapse with excitatory inputs results in inhibition of MSNs through a mechanism
Exposure to cocaine leads to attenuation of postsynaptic potentials[42]	Action of cocaine leads to release of dopamine that acts on spines of MSNs that synapse with excitatory inputs and results in attenuation of postsynaptic potentials
In response to natural rewards and cocaine exposure, a major set of MSNs show depression of firing rate[43-46]	Rewards and drugs cause release of dopamine from VTA and dopamine’s action on spines of MSNs that synapse with excitatory inputs result in reduced firing rate of MSNs through a mechanism
Synchronization of membrane potential states in a population of NAc neurons[53]	A mechanism through gap junctions between inhibitory neurons in VTA that provides inputs to NAc neurons and/or a mechanism at the level of spines of MSNs
Brain functions occur optimally in a narrow range of frequency of oscillating extracellular potentials especially that of background alpha rhythm as evident from electroencephalogram (EEG) findings[49]	Regional oscillations of extracellular potentials are expected to be related to oscillating extracellular potentials of the system
Summary of findings	Inter-connected constraints
Drugs cause release of dopamine from VTA, which in turn cause attenuation of postsynaptic potentials and depression of MSNs in NAc. Application of energy is able to induce delayed LTD through scaled up changes expected to occur normally at the synaptic region of NAc, which is likely responsible for generating internal sensation of pleasure	Dopamine does certain unique changes at the spines of MSNs of NAc that synapse with excitatory inputs to cause attenuation of postsynaptic potentials, depression of MSNs and promotes experimental induction of LTD. This inter-connected operation is expected to explain a mechanism that generates inner sensation of pleasure

Constraints provided by disparate findings can be used to find inter-connectable explanations for deriving a unique mechanism, which is expected to provide an explanation for the generation of internal sensation of pleasure. NAc: Nucleus accumbens; LTD: Long-term depression; MSNs: Medium spiny neurons; NMDA: N-methyl-D-aspartate; VTA: Ventral tegmental area.