Posted comment on ´Prior cocaine exposure increases firing to immediate reward while attenuating cue and context signals related to reward value in the insula` written by H.J. Pribut, D. Vazquez, A.T. Brockett, A.D. Wei, S.S. Tennyson and M.R.Roesch and published in Journal of Neuroscience 2021 41 (21) p. 4667 doi 10.1523/JNEUROSCI.3025-20.2021
SUMMARY
Pribut and colleagues investigated the role of the rat insula in a reward-guided decision-making task and how chronic cocaine exposure influenced the functionality of that area.
The group`s experimental set-up involved 9 rats that were initially trained on a reward guided decision-making (delay, size) task for 1 month before surgery. The water-deprived rats learnt to poke their noses in a port where they received one of three possible odor cues (2-octanol, pentyl acetate, carvone) which dictated in which direction the rats had to move in order to receive a liquid sucrose reward. Two odors instructed the rats to go either left or right for the reward (forced choice) and the other odor indicated that the rat could receive the reward from either well (free choice). The odors were presented in a random sequence except for the free choice odor which was presented every 7 out of 20 trials. Only correct well selection in forced choice trials led to the rat receiving the sucrose reward. The value of the reward and delay were independently manipulated across 4 blocks of 60 trials. For the first 2 blocks, one well delivered the reward immediately (500ms delay, 0.05ml – high reward) and the other delivered the reward with increasing delays (1000-7000ms). The delay times for the wells were switched in the remaining blocks so that the rats could learn a specific pattern of reward.
For the cocaine exposed rats, after a week of recovery following surgery to implant catheters and electrodes, the rats carried out a 12 point self-administration protocol in a conditioning chamber. The rats pressed levers in order to obtain either cocaine (days 1-6 1mg/kg per lever press for a maximum of 30 infusions or for a 3hr time limit and then for days 7-12, 0.5mg/kg per lever press for a maximum of 60 presses) or sucrose pellets (same schedule, but 2 pellets for days 1-6 and only 1 for days 7-12). After the self-administration protocol the rats were then left for a one month withdrawal period. Single unit recordings were then carried out according to electrode placements and the results analysed. The percentages of correct responses on the forced choice trials and the percentage of trials in which the rats chose a particular valued condition (short, long, large, small) were calculated along with the reaction times (odor offset to odor port exit). All results were averaged across all sessions and then statistical analyses were carried out.
For the neural activity measurements, activity (defined as total number of spikes divided by time followed by normalising) was analysed in 3 non-overlapping epochs: baseline firing rate taken 1 sec before odor presentation; odor cue onset taken 100ms after odor onset until port exit; and reward onset taken 250 msecs before sucrose delivery to 1 sec after reward delivery. This latter measurement was set-up to indicate activity related to reward expectancy and delivery. Significance in firing rates was determined by taking difference scores for each neuron and plotting the number of neurons with significantly different firing from the baseline. Following completion of the behavioural and neural activity studies, histological examination of the various brain areas was then carried out.
Previous results from behavioural experiments showed that rats prefer immediate reward over delayed reward and large reward over small ones and they are more motivated during size block contexts. In Pribut and team`s experiments the rats have to choose between immediate and delayed reward or have to choose between a large and small reward with delays to reward held constant. The rats learn which choice gives the preferred outcome and they maintain those expectations during delays to reward and across the trial blocks. The results from 416 cocaine recording sessions showed that in the free choice trials there was a significant effect on value with the selection of high value rewards in both delay and size blocks being greater. The cocaine exposed rats showed an even stronger preference for high value rewards and this was shown in the difference between high (short, big – around 60%) and low (long, small – around 40%) value free choice responses between them and the control rats. There was also a difference in reaction times. All rats increased speed for the high-valued rewards during the forced choice trials and were faster for size compared with the delay blocks. However, the cocaine self-administered rats were even faster than the controls and showed also a stronger response bias for high- versus low-value rewards. These findings supported the observations from others. Pribut and team also reported that their study, in contrast to others, that the self-administered cocaine rats were more accurate on the forced choice trials with significant effects of size blocks and high-value rewards (around 80% for cocaine exposed compared to control, 70%). The cocaine rats also followed the forced choice rules more accurately and adhered more strongly to the stimulus response contingencies than the controls.
Results from Pribut`s neural activity studies showed that the cocaine exposed rats had fewer cue-responsive cells than the controls since only 12% of neurons were responsive during odor sampling in the cocaine exposed rats compared to 28% active in the control. Further analysis of firing for high and low value rewards for delay (delay index = short – long / short + long) and size blocks (size index = big – small /big + small) gave value selectivity during the odor epoch (odor onset to port exit). The cocaine exposed rats showed no significant shifts in either delay or size indices and neither were the levels significantly different from the control distributions. The control rats on the other hand showed significant positive shifts in delay and size indices which indicated a higher frequency of neurons with stronger firing rates to cues that predicted high value reward within size and delay trial blocks. Therefore, Pribut and team concluded that the administration of cocaine led to decreased value encoding during the odor sampling instigated by reducing the numbers of odor responsive neurons and by only slightly reducing the outcome selectivity in the remaining neurons.
Pribut and team then looked at immediate rewards and activity during the anticipation and then delivery of that reward. In the control rats 46% of the neurons showed increased firing during the reward epoch which counted as 250ms before reward delivery to 1 second after reward delivery whereas in the cocaine administered rats there was only a 18% increase. The proportion of reward responsive neurons was, however in the cocaine administered rats higher. Examination of the single cells showed that many cells fired in anticipation of rewards across long delays, hence showing sustained firing from well entry until reward delivery. However, other cells exhibited increased firing after well entry at the time when reward would have been delivered for the majority of cells (ie. after 500msecs). Hence, these neurons were not capable of representing reward across a long delay. When the average firing was aligned to the well entry and reward delivery it was found that the control rats had insula neurons that exhibited sustained increased firing during long delays starting at well entry. The anticipatory firing after well entry for these insula neurons increased faster for rewards presented after a short delay than those for the longer delays. In the case of the cocaine exposed rats, the anticipatory firing for the short delay and long delays were the same with the peak being around the time when the more immediate reward would have been delivered. The firing then decreased. This indicated to the authors that the firing after cocaine exposure held on to the expectation that the reward would be delivered after a shorter delay which occurred in three (short, big, small) of the trial set-ups.
Quantification of the differences in firing of insula neurons from cocaine exposed rats to control rats with regards to firing strength and delay was carried out by the authors and this too supported the single cell response results. The difference in activity between the first and last 500ms of the delay period (late – early / late + early; early = first 500ms and late = last 500ms before reward; when the rats stay in the fluid well) of neurons presented with long delay rewards showed that for the control rats there was no significant difference in shift in the distribution. This indicated that the early and late expectancy related firing were similar across longer delays for the control rats. However, in the case of the cocaine exposed rats the distribution was not only different to the control rats, but also significantly shifted below zero. The authors explained the difference as a higher frequency of neurons of the cocaine exposed rats firing more strongly at the start compared with the end of the long delay.
The next experiments performed were to examine the average firing rates for reward delivery. It was expected that in the cocaine exposed rats, the ability of insula neurons to maintain anticipatory related firing from early to late delay would be impaired and this would translate into reduction in the neural representations of short delayed rewards compared with those after 500ms. For the cocaine exposed rats it was found that the average firing aligned to reward delivery which suggested that anticipatory firing for immediate rewards was stronger than for the delayed rewards. This effect was quantified by calculating the delay indices (short – long / short + long) which showed that the distribution of the firing of the cocaine exposed rats was significantly different to that of the control animals and had significantly shifted in the positive direction. This indicated to the authors that the cocaine exposure had increased the neural signals for the immediate rewards during the short delay trials and also over-represented the anticipation of more immediate rewards both within the long delay trials and when directly comparing immediate to delayed reward.
Pribut and team continued their investigation by looking at the context related value signals in relation to cocaine exposure. This was carried out because of an unexpected observation that insula neurons of the control rats had exhibited higher reward firing during size blocks (green and orange vs blue and red) and hence, had encoded block context. This was also seen for even small rewards (orange) of the same delay and size as trials with rewards with short delays (blue). These observations were quantified using a context index comparing average activity from size and delay blocks (size block – delay block / size block + delay block) 1- 2 seconds after reward, ie. when the rats were still consuming the sugar reward and were aware that reward had just been delivered. This indexed the global value differences between blocks. Pribut and team found that the insula neurons of the control rats showed positive shifts in distributions of activity which confirmed the unexpected observation of higher firing after reward delivery during size compared with delay blocks at the single neuron level. The cocaine exposed rat insula neurons did not demonstrate this effect and instead the context index distribution was significantly shifted below zero. This indicated that the cells tend to fire more strongly for delay blocks compared with size blocks. Neurons (22% of the total) in the control insula also increased firing in anticipation of house light onset which was the stimulus that signalled the start of each trial. These fired more strongly during the size blocks compared to the delay blocks. This observation was also quantified by computing the context index during the 4 secs before light onset which was the time period immediately preceding the onset of the trial. Again, a significant positive shift in firing rate distributions was observed which indicated that the insula neurons tended to fire more strongly during size compared with delay blocks before trial onset. However, in cocaine exposed rats, only 7% of neuronal cells showed the increased firing in anticipation of house light onset and these cells did not show a significant shift in context index distribution and was not significantly different from the controls. This indicated to the authors that the self-administration of cocaine led to a decrease in contextual pre-trial value encoding and this was achieved by reducing the counts of responsive neurons and slightly reducing the selectivity of those remaining.
The authors continued with an investigation of differences in firing between size and delay blocks to differences in percentage corrects and reaction times (size – delay /size + delay). With regards to percentage corrects, the control rats showed better performance since there were increases in firing and a significant positive relationship between size versus delay block accuracy and context encoding. However, in the cocaine exposed insula cells there was no correlation between firing and percentage correct. Similar observations were made with regards to reaction time. In the case of the control rats, there was a significant positive relationship between firing rate and reaction time for free choice trials whereas for cocaine exposure rats the relationship was disrupted. The authors interpreted these findings as stronger firing rates being actually related to slower reaction times during size blocks for the control rats which was not the case in cocaine exposed rats. Therefore, novel firing patterns are normally associated with accuracy and reaction time during a delay/size task, but this relationship is disrupted by pre-administration of cocaine.
Pribut and colleagues concluded their article with a discussion of their findings relating to the role of the insula in the executive processes involved in decision-making of reward-based tasks. The authors found that there are firing signals in the insula that relate to cues, context and differently valued rewards when the rats are presented with a reward-guided decision-making task. Signals representing rewards are increased especially those relating to delivery related processing of immediate reward. The insula encodes predicted outcomes during presentation of reward-predictive odor cues and fires in anticipation of reward after successful completion of the required action response. The firing is greater for cues that predict high value reward in both size and delay domains and the neurons involved here likely contribute to subjective preferences of immediate reward and maintenance of reward presentation across delays. The firing patterns seen in the insula were similar to those reported previously for two other brain areas (the orbitofrontal cortex and nucleus accumbens) which are also outcome-selective during cues and fire during anticipation and delivery rewards. However, whereas in these areas firing is not maintained at the same level with delay, firing in the insula is maintained at a level whether the reward delivery delay is long or short.
Firing of the insula neurons is also stronger during size blocks and correlates with changes in reaction time and accuracy. Pribut and colleagues then continued their discussion about how their experimental set-up was constructed in order to show this. For example, the set-up was constructed to rule out value manipulation and direction within the session. They used size blocks with larger rewards being received faster for those later in the task. These led to rats exhibiting faster reaction times and better accuracy later in the task because of the increased reward benefit for successful completion later on. This indicated that there were changes in overall value between delay and size blocks due to the experimental set-up which trigger increases in contextual firing observed. This finding supported the observation of higher firing occurring during size blocks before trial initiation as well as receiving larger rewards within the trial and delivery of small rewards eliciting firing of the same size as short-delay rewards. However, because the set-up essentially substitutes one natural value manipulation with another experimentally added one, there is a need to investigate the whole topic further. Therefore, Pribut and team concluded from their findings of insula activity correlating to reaction time and percentage correct that it is probably more accurate to hypothesise that the increases in activity correlate to the overall value of block contexts and contribute to elevating motivation as satiation sets in rather than the more normal situation of decreasing motivation for reward as a consequence of the rat receiving more and more reward as the trial session continues. Their findings were said to be in line with those seen with macaque insula neurons where there is a relationship between BOLD signalling and task engagement during blocks of trials where probability of reward receipt is either higher or lower (Wittman). Therefore, Pribut and colleagues concluded that their context effects suggested that the global reward signal representing both specific reward outcome as well as reward probability is encoded at the single cell level in the insula. This provides the evidence of the insula`s function in changing behaviour dependent on context-based adjustments to representations of reward value (Naqvi).
The second part of the discussion looked at the findings of the study on the effect of self-administered cocaine on insula functioning in the same reward guided decision-making task. Pribut and team found that the self-administration of cocaine under the conditions of the experiment led to a reduction in signals in the insula relating to cue and block context selectivity. This leads to an impairment of executive control and decision making in this type of reward-based task. They found that the cocaine exposed animals demonstrated a higher preference for high valued rewards and shifted the balance of encoding in the insula from cues and context to reward. It was found that fewer neurons increased firing to cues and context, but significantly more increased firing in anticipation of immediate reward. They also fired strongly at the start of long delay trials at the time when reward would have been delivered if the trial had been with a shorter delay. Such activity suggested that the inaccurate assessment of reward value (delay and size) at the time of decision-making and a stronger anticipation of reward could be the physiological reason why less favourable impulsive choices are made in reward-guided decision-making.
The effects on reward-guided decision-making by cocaine exposure also included faster reaction times and higher accuracy in size blocks. The insula neurons failed to increase firing at the end of the sessions during size trial blocks where normally it would be needed to motivate satiated animals to undertake the reward task. Pribut and team explained the absence of the increase as due to either a disruption in insular signals as part of the global reward signal related to satiety, motivation or absolute value which are necessary to drive behaviour during the size blocks, or that the signal is simply not necessary to drive motivation. However, Pribut and team found that the absence of the insula based global signals may in turn disrupt processing of long- versus short delay rewards and subsequently bias behaviour for immediate rewards.
Pribut and team then continued their discussion about their findings of greater accuracy and slower reaction times seen with higher rates of context encoding in the cocaine exposed rats. The authors described the observations as being counterintuitive at face value but suggested that the correlations may reflect the subtle increases in deliberation and attention necessary for performance as fatigue and satiety grows during the course of the session. They suggested the importance of the relationship between the insula cortex and anterior cingulate cortex (ACC) for attention and conflict especially since previous studies by the authors had indicated the impairment of attentional signals in the ACC after cocaine exposure (Vazquez). This was suggested as an area for future research as well as by looking at more specific areas of the insula cortex itself especially in the light of different functioning of the various sub-regions recorded for humans and primates, eg. ventral part of the anterior insula as being responsible for social-emotional processing and the dorsal region for cognition.
Therefore, to conclude Pribut and colleagues` findings showed that insula signalling in rats was involved in reward-guided decision making and this was affected by exposure to self-administered cocaine. The reward delivery related signals in cocaine exposed rats were enhanced whereas context and cue related firing were reduced, but cocaine exposed rats were more sensitive to value manipulations and were faster to respond. These changes were correlated to increased numbers of neurons in the insula that increased firing to reward. The neurons also fired more strongly at the start of the long-delay trials when a more immediate reward would be expected and fired less strongly in anticipation of the actual delivery of delayed rewards. Therefore, the altered insula firing activity is likely to contribute to impaired decision-making after cocaine use and leads to appropriately changed behaviour.
COMMENT
What makes this topic so interesting is that the insular cortex is a relatively minor area from a research perspective, but its activity is important in relating physical needs and emotional values to events. Therefore, the area`s activity is involved in decision-making and actions involving these types of influences, eg. reward guided decision making which was the subject of Pribut`s article. As humans we assume that emotional needs and values are dominant when making decisions that guide behaviour, but we also have physiological needs and these can come to the fore in a negative way with for example, drug addiction and caffeine consumption. We tend to think of these things as something that can be controlled or guided by the individual in a top-down manner, but these can also be related to physiological states and demands that are bottom-up and hence, decision-making is not quite as clear-cut as we think. And here, is where the insular cortex plays a role since it functions as an area that incorporates and exchanges information from bottom-up processes (more often physiological) and top-down processes (more often cognitive).
This primary capability of the insula cortex can be important in a wide number of different functions. Examples of physical conditions associated with insula functioning are auditory perception, information about heart rate and blood pressure and taste where the anterior insula is actually part of the primary gustatory cortex. Activity of the insula can also be seen in motor control contributing to hand-eye movement, swallowing and speech articulation. It can also be involved in the control of autonomic functions through its regulation of the sympathetic and parasympathetic systems, as well as regulating the immune system although this is likely to be indirect. However, other functions, more relevant to this blog, are related to the conscious awareness and emotional status roles in cognition such as that seen with anxiety. One of the basic functions attributed to it is interoception (interoceptive conscious awareness) which is where the insula provides a bridge between consciousness (conscious awareness), emotional awareness and real-time homeostasis and physiological status. We are used to thinking about emotions in terms of what we think about something, but emotional awareness attributed to insula functioning is more basic and relates to feelings to things like pain, temperature or touch and this comes from bottom-up informational processing. For example, fMRI studies have shown that there are overlapping neural activations in cingulate cortices and the insular cortex when individuals experience pain and others empathise that pain (Singer). However, the insula area is not devoid of input of emotional awareness and this occurs via the workings of the higher brain areas such as the orbitofrontal cortex which link the area to emotional value. The capability is achieved through its physiological structure with the posterior insular cortex linked to somatotopic representations of the physiological states such as with itching, pain etc. plus two-way connectivity to its other half, the anterior insular cortex which provides the connectivity to the higher brain areas associated with emotional value, eg. the prefrontal cortex and in particular, the orbitofrontal cortex (OFC). This provides the access to emotions and links activity to conditions such as empathy and compassion.
With reference to Pribut`s article this physiological need/emotional need bridging function of the insula is involved in reward guided decision-making where the reward is an incentive linked to a basic physiological need such as food or sleep. Insula activity is related to cues (the external event), context (including anticipation, delay) and differently valued rewards, eg. satiety will reduce its activity for food and water (Livneh) and as Pribut showed greater rat insular firing was observed with immediate large sugar rewards. It is therefore likely that the insula in this situation contributes to the global neuronal ´representation` of the decision-making task which in memory terms can be described as ´working memory`. Firing in this global working area occurs from the binding and integration of real-time information from a number of areas (Jang) such as the hippocampus and putamen (integrating event characteristics), primary visual cortex (feature selective firing – Leitao), posterior frontal cortex (category selective firing) as well as the firing of the insula, caudate, anterior cingulate cortex and parietal cortex all fulfilling task demands (eg. attention) (Corradi-Dell`Acqua). The insula appears to be involved specifically in mediating the retrieval of outcome values (Parkes) and it does this within its connectivity with the basal amygdala which is linked to value encoding and to the nucleus accumbens (NAc) (Parkes). This insula function appears to be dependent on NMDAR firing since the NMDAR antagonist ifenprodil abolishes the outcome effect (Parkes).
The various functions exhibited by the insular cortex are like other brain areas based on its physiological structure and firing capability. In the insular cortex these can be attributed to its anterior/posterior structure and connectivity, its specialised neuronal cells (the VENs) and its dopaminergic firing capability. The insular cortex consists of two parts (anterior – consisting of agranular cells and posterior – consisting of granular cells) with different connectivity and as given above different functioning. The posterior part is the simpler one with input from the ventral posterior inferior and ventral medial areas of the thalamus and brainstem, two-way connectivity with the somatosensory cortex and importantly to its other part, the anterior, as well as output to the lateral and central parts of the amygdala as well. This, as already described, is important for the internal representation of physiological information and homeostasis. However, the anterior part of the insular cortex has more wide-spread two-way connectivity to the amygdala, frontal lobe (OFC in particular), parietal lobe, temporal lobe, inferior frontal gyrus and cingulate cortex. Not only does this area differ in function according to region, eg. ventral part associated with socio-emotional status and the dorsal part with cognition, but also its volume exhibits a positive correlation with accuracy in the subjective sense of the internal status (Droutman). Such complexity supports its role in its association with the emotional value of rewards, achieved by acting as an interface between the interoceptive input from the thalamus and brain stem and the top-down processing of goals, values and attention.
The second physiological feature that contributes to the insula in its functioning is the presence of specialised neuronal cells known as von Economo neurons (VENs) which are large spindle shaped cells found in the fifth layer (Vb) of the insular cortex of the anterior side and particularly in high density in the right frontal region. These cells are also seen in the anterior cingulate cortex and OFC and occur when there is ´long` connectivity with cells approx. 4.6 times the size of neighbouring pyramidal cells. This makes this type of neuronal cell ideal for rapid, long-distance transmission and integration of information, important for the insular cortex in its role in the global neural representation of the working memory. The firing of the cells has also been proposed as also leading to alleged resonating areas which have been suggested as underlying the cognitive impression of emotions (LaBerge). Electric resonating has been associated with the apical dendrites of the pyramidal neurons extending upwards into the cortex and embedded in the recurrent corticothalamic circuits. It is suggested as enhancing the intensity and duration of electrical activity of a neuron over a narrow frequency range. Separation of this central resonating circuit from the surrounding processing network has been proposed as representing the ´having` of the subjective impression from the ´thinking` about them (LaBerge).
Another physiological aspect aiding the physiological/emotional bridging function of the insular cortex is its dependence on dopamine (DA), which often appears in connection with emotional states and reward pathways. Some examples of reward linked dopaminergic system changes are: depression of the dopamine neurons occurs when an expected reward fails to appear or has an extended delay before its appearance; an unpredicted reward can elicit an activation (positive prediction error); a predicted reward can elicit no response; a phasic DA response can occur when rewards differ from prediction (reward prediction error); and an increase in DA can lead to sensitisation which may strengthen learning. This may result in dysfunction in the cortical regions and lead to compulsive reward seeking and consumption (eg. drug addiction). In the case of Pribut`s test rats and their reward of sucrose solution when the animal is presented with the primary reinforcer (the sucrose solution), DA is released and the dopaminergic system responds setting up firing connectivity to the higher brain areas, eg. NAc and PFC and the appropriate hierarchy of information flow. In the case of NAc, projections to the dorsal striatum and ventral striatum (NAc) evoke independent actions on learning the association between action and reward. The NAc is linked to the transfer of new learning and the dorsal striatum linked to the automated processes of learning and maintenance of information regarding reward outcomes. Dopaminergic firing of the PFC area is associated with preparation of movement, goal achievement and the motivational value of rewards. With regards to the insular cortex and dopamine receptors, both DA1 and DA2 receptors are present in this area with the DA1 receptors linked to reward (eg. nicotine) and DA2 with novelty seeking personality traits (Suhura). Therefore, as we see with Pribut`s cocaine administration experiments, alterations to the dopamine system can have knock on effects on behaviour, eg. on conditional learning and this is linked to the cocaine induced changes in the dopaminergic system.
However, insula region activity is not confined to dopamine alone since other active neurotransmitters are also reported, eg. glutamate and 5HT. In the case of glutamate, the connectivity between the basal amygdala and insular cortex is glutamatergic with tetanic stimulation of the amygdala inducing LTP in the insular cortex in a NMDAR dependent manner. This is involved in the consolidation of memories for those seen in conditioned taste aversion for example (NMDAR and muscarinic receptor activation – Gil-Lievana, Parkes). The effect is complex since it is refined by muscarinic receptors being responsible for the immediate learning of a pleasurable novel taste (the effect is blocked by the muscarinic antagonist, scopolamine – Parkes), whereas the administration of the NMDAR antagonist AP5 blocks only the conditioned taste aversion. This suggests that long-term memory storage and memory retrieval involves the NMDAR of the insular cortex whereas single taste awareness involves muscarinic receptors (Parkes). The situation with 5HT and 5HTR binding in the insular cortex is also complex. For example, in the case of anxiety (Ju) a difference in receptor population activity is exhibited. More than 70% of glutamatergic neurons in specific neuronal populations of the insula (insular projection neurons to the central or basolateral amygdala nuclei or to the rostral and caudal parts of the lateral hypothalamus) express the 5HT1A R in comparison to only 30% of GABAergic neurons. The same proportions and area specificity are also observed with the 5HT2A R (Ju). This indicates that most of the glutamatergic neurons present in the insular cortex can be affected by 5HT via interaction with both 5HT1A and 5HT2A receptors whereas effects on GABAergic neurons is more limited.
Therefore, the role of the insular cortex as interface between emotional and physiological information relies on its physiological structure being optimised for the demands placed upon it and this means a ´balanced` neurochemical system of firing and connectivity within its global framework. As Pribut`s study showed this ´balance` can be upset and this may then manifest into alterations in neurochemical activity and ultimately, behaviour.
Pribut`s study focused on one type of task (reward guided conditioning task) and one example of effect (cocaine pre-administration). The experimental set-up was a variation of conditioned place preference relating to sucrose solution reward and this behavioural test was carried out with or without pre-administration of cocaine. In both cases, repetition of the reward leads to increased wanting of it, which is known to be mediated by dopamine, balanced against increased satiety which would decrease motivation to seek it out and decreased liking which would lead to tolerance. Therefore, the experimental set-up was adjusted so that motivation remained comparable for the whole test period. The motivation of the rat to seek out the reward and move as instructed (left or right) complies to the forward movement theory for addiction and motivation. This theory proposes that the rat is motivated to eat and drink via activation of the hypothalamus and dopaminergic system. In order to fulfil this ´want` then the rat moves towards the food/drink (forward movement) and hence, the sugar reward is the positive reinforcer and the incentive is the anticipation of reward. The neurochemical pathways for forward motion are the mesolimbic system (VTA to NAc) in which low doses of positive reinforcers produce forward movement and the nigrostriatal system (substantia nigra to caudate) where large doses increase small, localised movements. In the case of Pribut`s rats in the execution of their reward-guided decision-making task, the reward of the sugar solution fulfils a physiological need and therefore, the insula cells responding to the stimulus are likely to be on the posterior side with firing connectivity to the somatosensory cortex and lateral amygdala and input coming from the brain stem and thalamus (ventral posterior inferior and ventral medial regions). Since the posterior and anterior parts are widely connected the information is passed from the posterior part to the anterior and then onto the anterior-associated brain areas. Only 28% of cells appear to be involved in this particular reward-guided function according to Pribut`s experiments.
The pre-administration of cocaine leads to changes in the observed neuronal firing of the insula region and therefore, as a consequence of this, behavioural actions are also affected. The number of cells firing in the execution of Pribut`s study task drops from the 28% to only 12%. This means that the cocaine pre-administration has had a long-term effect on firing capability within the insula. Although the number of firing cells appears decreased, firing is actually stronger at the start than that of the control rats plus the firing is also not maintained with delay indicating that the anticipatory effect is not carried on. For both control and cocaine pre-administered rats larger rewards elicit stronger firing than smaller rewards. Since cocaine affects the dopaminergic systems then it can be assumed that it is those that are affected by the pre-administration and that the cocaine in Pribut`s experiments should be regarded as a dopamine ´agonist` rather than from the perspective of emotions attributed to its recreational use in humans. Since cocaine is known to block the re-uptake of dopamine (via the dopamine transporter – Verma) its effect is elicited through the increased concentration of dopamine in the synapse and action at the DA2R subtype of dopamine receptor (binds to the DA2-sigma1 receptor complex inhibiting its function) and not the DA1. Chronic cocaine leads to a down regulation of the DAR number and/or release systems.
Hence, it can be assumed that in Pribut`s experiments the cocaine pre-administration either has direct effects on the dopaminergic system in the insular cortex and/or it has indirect effects on other dopaminergic dominant areas connected with the insula region. It has already been given that cocaine can cause direct effects on dopamine uptake and dopamine receptor number in the insula. The increased firing observed by Pribut implies that the dopaminergic system based firing under normal conditions has been removed and the ´balance` of the area`s firing is shifted to non-dopamine dependent excitatory pathways. Therefore, it is likely that a maximum of 16% of cells in the insula taking part in firing associated with reward guided decision making are DA2R dominant and these perform some overall ´inhibitory` action (eg. output firing is reduced) on firing of connected areas (eg. amgydala, temporal lobe, OFC, parietal lobe) under normal circumstances. With reduced dopamine receptor firing, it is likely that the excitatory glutamate firing then dominates. It has been suggested that under normal conditions there is a balance between DA1R controlled reward seeking firing and DA2R controlled aversion and cocaine upsets this balance by causing the DA1R to dominate (Navarro). However, cocaine also blocks dopamine uptake leading to an increase in dopamine in the synapse and a subsequent down-regulation of dopamine receptors. Therefore, this might be an acceptable explanation for single-dose cocaine administration, but Pribut`s study involved chronic administration of cocaine before testing took place.
The nature of the firing also changed in Pribut`s study with regards to timing of rewards. Strong firing was seen at the beginning with both cocaine pre-administered rats and control rats which implies that at the beginning, the firing mechanisms involved in the initial assessment of value and motivation to move and drink appear to be not dependent on dopamine. It is likely that the glutamate, muscarinic acetylcholine systems are dominant in the insula at this time. With time (observed by introducing delay in the delivery of reward), the strong firing observed in cocaine pre-administered rats diminishes. This is interpreted as the assessment of initial value of the reward not being affected by cocaine pre-administration, but the maintenance of this value is (ie. the anticipation decreases as the reward is not forthcoming). Therefore, the dopamine system of the insular cortex is likely to be involved in the maintenance of the value assessment (anticipation) and monitoring of value assessment. From a neurochemical perspective this would involve dopaminergic excitatory output firing to the connected areas (eg. OFC, amygdala) and is likely since assessment of reward relative to time of delivery would involve higher brain area processing (eg. working memory, memory recall).
The other way in which the pre-administration of cocaine can affect insula firing is indirect in that the cocaine administration can affect the dopaminergic systems of the other areas which provide input into the insula, eg. the amygdala, OFC, parietal cortex plus others which exhibit two-way connectivity with the insula. This would mean that a reduction in DA dependent input on cocaine pre-administration would strengthen the firing of non-dopamine dependent systems in the insula. Again, this supports the view that since the initial value is not affected (stronger firing), it is the monitoring of value with time that is dependent on dopaminergic firing.
The observations by Pribut on firing of the insula are similar to the reports on firing observed in the connected OFC and NAc areas under the same demands. These areas are also known for their value assessment and outcome functions. However, from a neurochemical perspective they differ from the insula in that they do not under normal circumstances maintain their firing at the same level with delay of reward delivery. This is contrary to the insula which does and indicates that the insula contribution to the global assembly (working memory) neural representation maintains the reward value independent of time, but dependent on dopamine system activation whereas the OFC and NAc firing is more subtle. When the dopaminergic firing is removed then the insula region acts in the same manner as the OFC and NAc and firing therefore, in these regions is likely not to be reliant on dopaminergic systems and is more complex. These areas are influenced by perhaps by input that is related directly to real-time input, assessment (attention and working memory) and immediate feedback mechanisms (conflict with ACC connectivity). This view is supported by reports that glutamate systems in addiction affecting basal amygdala activity leads to the induction of long-term potentiation (LTP) in a NMDAR dependent manner in the insula cortex.
The firing interconnectivity of the insular cortex and other areas given above in reward-guided decision-making is supported by observations of behaviour. From a behaviour perspective, the initial value of the reward is not affected by cocaine pre-administration, but the assessment of it with time is because activity in the insular cortex decreases. This means that the insula plays a role in the global firing assembly representing reward value but if its contribution is disrupted then processing of delayed rewards is detrimentally affected and event values in this case decrease. This would have the ultimate effect that behaviour would favour immediate rewards and value will decrease with delay in delivery. This is mirrored by observations that NAc activity with cocaine pre- administration leads to a decreased motivation to work ie. value decreased and that repeated exposure to cocaine leads to a reduction in reward value (Halbout). However, other research shows that it appears that rats are acutely aware of this devaluation (Halbout) and can adapt behaviour accordingly. Pribut found evidence to support this in that cocaine pre-administered rats are more accurate and exhibit quicker reaction times than controls. Other observations are that DA antagonists increase the activity observed with cocaine and lever pressing and that cocaine administration leads to a skewing of reward values where riskier rewards are accepted initially (Iowa gambling task, although this is an acute treatment rather than a long-term effect as described in Pribut`s experiments – Vadhan). Hence, this implies that reward systems are more attuned with dopamine-deficient activity and that dopaminergic systems in the insula are likely to affect the assignment of reward value over time (anticipation) rather than initial reward value.
Therefore, it can be summarised that the insular cortex is an area that forms an ´interface` between bottom-up incoming information about the physiological status and top-down incoming information about emotional awareness and value of that information. In doing so it forms part of the global assembly of firing neurons that form the neural representation of the information and allows processing to take place that contribute to the basis of the behavioural action. The example studied in Pribut`s experiments, reward guided decision-making, is ideal in demonstrating the demands of this type of functioning with the reward being food-based and the anticipation of reward via the delivery delay represented by top-down area activity. What may be concluded is that the whole process of reward value assessment, monitoring and consequent action is complex and cannot be attributed to activity in one brain area alone or one neurotransmitter. The dopaminergic system associated with areas like the OFC, amygdala, insula gives only one aspect of the firing systems and area connectivity in play and is likely to be situation-dependent with different balances and different area connectivity responsible and active in particular situations. With reference to Pribut`s study and reward-guided decision-making in rats, the mechanisms in play and behavioural consequences when dopaminergic systems are disrupted may be clearly displayed, but the transfer of the conclusions to other situations and especially other species may not be valid. Therefore, studies of reward and decision-making whether from a neurochemical perspective or behavioural perspective should be carefully constructed and results interpreted in detail in order that the appropriate neurochemical mechanisms and brain activity firing patterns can be accurately deduced and explained. From this will come a more accurate understanding of the neurochemical basis of behaviour and if relevant, more appropriate medication or behavioural therapy.
Since we`re talking about the topic ………………………………..
……..amphetamine also acts on the dopamine system causing a release of dopamine from vesicles and an increase of the neurotransmitter in the synapse. If Pribut`s experiments are repeated, can we assume that the same firing and behavioural patterns would be observed as with cocaine since essentially the neurochemical affect in the insula is the same?
……….would it be possible to carry out experiments like Pribut`s involving reward guided decision-making with individuals if a short acting enhancer like caffeine or appetite enhancer is given instead of cocaine and the decision-making task restricted to a 3D virtual reality task so that ´forward motion` is required?
………some decision-making is said to be affected by age although reports are not conclusive (Fernades – decisions under uncertainty then older adults more risk seeking; decisions under risk with outcomes known then similar performance). Therefore, if Pribut`s experiments were repeated but with aged mice, can we assume that we would see not see changes in behaviour or firing compared to the control since the outcomes are still the same and age would only reduce overall levels of performance for both the cocaine-pre-administered mice and the controls?
neurochitchat 