The immunomodulatory effect of oral NaHCO3 is mediated by the splenic nerve: multivariate impact revealed by artificial neural networks.

Stimulation of the inflammatory reflex (IR) is a promising strategy for treating systemic inflammatory disorders. Recent studies suggest oral sodium bicarbonate (NaHCO3) as a potential activator of the IR, offering a safe and cost-effective treatment approach. However, the mechanisms underlying NaHCO3-induced anti-inflammatory effects remain unclear. We investigated whether oral NaHCO3's immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO3 or water (H2O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO3 led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFα + (M1-like) macrophages, M1-like/M2-like ratio, and SSChigh/SSClow ratio of FSChighCD11bc + cells, decreased in the spleen following NaHCO3 administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO3-induced immunomodulation. Artificial neural networks accurately classified NaHCO3 and H2O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO3-induced immunomodulatory changes to the spleen, emphasizing NaHCO3's potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.

OFC neurons do not represent the negative value of a conditioned inhibitor.

The orbitofrontal cortex (OFC) is often proposed to function as a value integrator; however, alternative accounts focus on its role in representing associative structures that specify the probability and sensory identity of future outcomes. These two accounts make different predictions about how this area should respond to conditioned inhibitors of reward, since in the former, neural activity should reflect the negative value of the inhibitor, whereas in the latter, it should track the estimated probability of a future reward based on all cues present. Here, we assessed these predictions by recording from small groups of neurons in the lateral OFC of rats during training in a conditioned inhibition design. Rats showed negative summation when the inhibitor was compounded with a novel excitor, suggesting that they learned to respond to the conditioned inhibitor appropriately. Against this backdrop, we found unit and population responses that scaled with expected reward value on excitor + inhibitor compound trials. However, the responses of these neurons did not differentiate between the conditioned inhibitor and a neutral cue when both were presented in isolation. Further, when the ensemble patterns were analyzed, activity to the conditioned inhibitor did not classify according to putative negative value. Instead, it classified with a same-modality neutral cue when presented alone and as a unique item when presented in compound with a novel excitor. This pattern of results supports the notion that OFC encodes a model of the causal structure of the environment rather than either the modality or the value of cues.

Can a basic solution activate the inflammatory reflex? A review of potential mechanisms, opportunities, and challenges.

Stimulation of the inflammatory reflex (IR) is a promising strategy to treat systemic inflammatory disorders. However, this strategy is hindered by the cost and side effects of traditional IR activators. Recently, oral intake of sodium bicarbonate (NaHCO3) has been suggested to activate the IR, providing a safe and inexpensive alternative. Critically, the mechanisms whereby NaHCO3 might achieve this effect and more broadly the pathways underlying the IR remain poorly understood. Here, we argue that the recognition of NaHCO3 as a potential IR activator presents exciting clinical and research opportunities. To aid this quest, we provide an integrative review of our current knowledge of the neural and cellular pathways mediating the IR and discuss the status of physiological models of IR activation. From this vantage point, we derive testable hypotheses on potential mechanisms whereby NaHCO3 might stimulate the IR and compare NaHCO3 with classic IR activators. Elucidation of these mechanisms will help determine the therapeutic value of NaHCO3 as an IR activator and provide new insights into the IR circuitry.

Dissociation of Appetitive Overexpectation and Extinction in the Infralimbic Cortex.

Behavioral change is paramount to adaptive behavior. Two ways to achieve alterations in previously established behavior are extinction and overexpectation. The infralimbic (IL) portion of the medial prefrontal cortex controls the inhibition of previously established aversive behavioral responses in extinction. The role of the IL cortex in behavioral modification in appetitive Pavlovian associations remains poorly understood. Here, we seek to determine if the IL cortex modulates overexpectation and extinction of reward learning. Using overexpectation or extinction to achieve a reduction in behavior, the present findings uncover a dissociable role for the IL cortex in these paradigms. Pharmacologically inactivating the IL cortex left overexpectation intact. In contrast, pre-training manipulations in the IL cortex prior to extinction facilitated the reduction in conditioned responding but led to a disrupted extinction retrieval on test drug-free. Additional studies confirmed that this effect is restricted to the IL and not dependent on the dorsally-located prelimbic cortex. Together, these results show that the IL cortex underlies extinction but not overexpectation-driven reduction in behavior, which may be due to regulating the expression of conditioned responses influenced by stimulus-response associations rather than stimulus-stimulus associations.

The basolateral amygdala is necessary for negative prediction errors to enhance cue salience, but not to produce conditioned inhibition.

Behavioral evidence shows that prediction errors (PEs) not only drive associative learning, but also enhance the salience of predictive cues, making them better able to capture attention when they are next encountered. Research from our laboratory suggests that this latter consequence of PEs depends on a neural circuit that includes the amygdala. Lesions of the basolateral complex of the amygdala (BLA), for instance, selectively disrupt enhancements in cue processing that are normally induced by positive PEs without compromising simple excitatory learning. This result is consistent with electrophysiological evidence showing that BLA neurons track positive PEs. Interestingly, the same neurons also seem to track negative PEs, suggesting the possibility that the BLA might also use these errors to drive enhancements in cue processing. Here, we examined the role of the BLA in the processing (Experiment 1) and utilization (Experiment 2) of negative PEs in increasing cue salience in an unblocking procedure. Using FOS expression as an index of neural activity, Experiment 1 confirmed that BLA neurons track negative PEs with reinforcement downshifts. This tracking was evident both when these errors were generated by decreasing the concentration of a sucrose reinforcer (which encourages the development of conditioned inhibition) and when they were generated by decreasing the number of sucrose reinforcers (which encourages excitatory learning - unblocking - and allows the detection of enhancements in cue processing). Experiment 2 demonstrated that BLA lesions abolished enhancements in cue processing while sparing inhibitory learning. These results suggest a general role of the BLA in utilizing PEs, whatever their sign, for boosting cue processing.

Normal aging alters learning and attention-related teaching signals in basolateral amygdala.

Normal aging has been associated with an increased propensity to wait for rewards. When this is tested experimentally, rewards are typically offered at increasing delays. In this setting, persistent responding for delayed rewards in aged rats could reflect either changes in the evaluation of delayed rewards or diminished learning, perhaps due to the loss of subcortical teaching signals induced by changes in reward; the loss or diminution of such teaching signals would result in slower learning with progressive delay of reward, which would appear as persistent responding. Such teaching signals have commonly been reported in phasic firing of midbrain dopamine neurons; however, similar signals have also been found in reward-responsive neurons in the basolateral amygdala (ABL). Unlike dopaminergic teaching signals, those in ABL seem to reflect surprise, increasing when reward is either better or worse than expected. Accordingly, activity is correlated with attentional responses and with the speed of learning after surprising increases or decreases in reward. Here we examined whether these attention-related teaching signals might be altered in normal aging. Young (3-6 months) and aged (22-26 months) male Long-Evans rats were trained on a discounting task used previously to demonstrate these signals. As expected, aged rats were less sensitive to delays, and this change was associated with a loss of attentional changes in orienting behavior and neural activity. These results indicate that normal aging alters teaching signals in the ABL. Changes in these teaching signals may contribute to a host of age-related cognitive changes.

Persistent disruption of overexpectation learning after inactivation of the lateral orbitofrontal cortex in male rats.

RATIONALE AND OBJECTIVE: Learning to inhibit acquired fear responses is fundamental to adaptive behavior. Two procedures that support such learning are extinction and overexpectation. In extinction, an expected outcome is omitted, whereas in overexpectation two individually trained cues are presented in compound to induce an expectation of a greater outcome than that delivered. Previously, we showed that inactivation of the lateral orbitofrontal cortex (lOFC) in experimentally naïve male rats causes a mild impairment in extinction learning but a profound one in overexpectation. The mild extinction impairment was also transient; that is, it was absent in a cohort of rats that had prior history of inhibitory training (overexpectation, extinction) and their associated controls. This raised the question whether lOFC involvement in overexpectation could likewise be attenuated by prior experience. METHODS: Using a muscimol/baclofen cocktail, we inactivated the lOFC during overexpectation training in rats with prior associative learning history (extinction, overexpectation, control) and examined its contribution to reducing learned fear. RESULTS: Inactivating the lOFC during compound training in overexpectation persistently disrupted fear reduction on test in naïve rats and regardless of prior experience. Additionally, we confirm that silencing the lOFC only resulted in a mild impairment in extinction learning in naïve rats. CONCLUSION: We show that prior associative learning experience did not mitigate the deficit in overexpectation caused by lOFC inactivation. Our findings emphasize the importance of this region for this particular form of fear reduction and broaden our understanding of the conditions in which the lOFC modulates behavioral inhibition.

The Recruitment of a Neuronal Ensemble in the Central Nucleus of the Amygdala During the First Extinction Episode Has Persistent Effects on Extinction Expression.

BACKGROUND: Adaptive behavior depends on the delicate and dynamic balance between acquisition and extinction memories. Disruption of this balance, particularly when the extinction of memory loses control over behavior, is the root of treatment failure of maladaptive behaviors such as substance abuse or anxiety disorders. Understanding this balance requires a better understanding of the underlying neurobiology and its contribution to behavioral regulation. METHODS: We microinjected Daun02 in Fos-lacZ transgenic rats following a single extinction training episode to delete extinction-recruited neuronal ensembles in the basolateral amygdala (BLA) and central nucleus of the amygdala (CN) and examined their contribution to behavior in an appetitive Pavlovian task. In addition, we used immunohistochemistry and neuronal staining methods to identify the molecular markers of activated neurons in the BLA and CN during extinction learning or retrieval. RESULTS: CN neurons were preferentially engaged following extinction, and deletion of these extinction-activated ensembles in the CN but not the BLA impaired the retrieval of extinction despite additional extinction training and promoted greater levels of behavioral restoration in spontaneous recovery and reinstatement. Disrupting extinction processing in the CN in turn increased activity in the BLA. Our results also show a specific role for CN PKCδ+ neurons in behavioral inhibition but not during initial extinction learning. CONCLUSIONS: We showed that the initial extinction-recruited CN ensemble is critical to the acquisition-extinction balance and that greater behavioral restoration does not mean weaker extinction contribution. These findings provide a novel avenue for thinking about the neural mechanisms of extinction and for developing treatments for cue-triggered appetitive behaviors.

Surprise! Neural correlates of Pearce-Hall and Rescorla-Wagner coexist within the brain.

Learning theory and computational accounts suggest that learning depends on errors in outcome prediction as well as changes in processing of or attention to events. These divergent ideas are captured by models, such as Rescorla-Wagner (RW) and temporal difference (TD) learning on the one hand, which emphasize errors as directly driving changes in associative strength, vs. models such as Pearce-Hall (PH) and more recent variants on the other hand, which propose that errors promote changes in associative strength by modulating attention and processing of events. Numerous studies have shown that phasic firing of midbrain dopamine (DA) neurons carries a signed error signal consistent with RW or TD learning theories, and recently we have shown that this signal can be dissociated from attentional correlates in the basolateral amygdala and anterior cingulate. Here we will review these data along with new evidence: (i) implicating habenula and striatal regions in supporting error signaling in midbrain DA neurons; and (ii) suggesting that the central nucleus of the amygdala and prefrontal regions process the amygdalar attentional signal. However, while the neural instantiations of the RW and PH signals are dissociable and complementary, they may be linked. Any linkage would have implications for understanding why one signal dominates learning in some situations and not others, and also for appreciating the potential impact on learning of neuropathological conditions involving altered DA or amygdalar function, such as schizophrenia, addiction or anxiety disorders.

Modeling attention in associative learning: two processes or one?

Certain studies of associative learning show that attention is more substantial to cues that have a history of being predictive of an outcome than to cues that are irrelevant. At the same time, other studies show that attention is more substantial to cues whose outcomes are uncertain than to cues whose outcomes are predictable. This has led to the suggestion of there being two kinds of attention in associative learning: one based upon a mechanism that allocates attention to a cue on the basis of its predictiveness, the other based upon a mechanism that allocates attention to a cue on the basis of its prediction error (e.g., Le Pelley, Quarterly Journal of Experimental Psychology, 57B, 193-243, 2004). As an alternative, it has been demonstrated that the effects of both predictiveness and uncertainty can be accounted for with only one kind of attention: one that emphasizes the role of prediction (Esber & Haselgrove, Proceedings of the Royal Society B, 278, 2553-2561, 2011). Here, we consider the alternative: whether the effects of predictiveness and uncertainty can be reconciled with a model of learning that emphasizes the role of prediction error (Pearce, Kaye, & Hall, 1982). Simulations of this model reveal that, in many cases, it too is able to account for the influence of predictiveness and uncertainty in associative learning.

Surprise-induced enhancements in the associability of Pavlovian cues facilitate learning across behavior systems.

Surprising violations of outcome expectancies have long been known to enhance the associability of Pavlovian cues; that is, the rate at which the cue enters into further associations. The adaptive value of such enhancements resides in promoting new learning in the face of uncertainty. However, it is unclear whether associability enhancements reflect increased associative plasticity within a particular behavior system, or whether they can facilitate learning between a cue and any arbitrary outcome, as suggested by attentional models of conditioning. Here, we show evidence consistent with the latter hypothesis. Violating the outcome expectancies generated by a cue in an appetitive setting (feeding behavior system) facilitated subsequent learning about the cue in an aversive setting (defense behavior system). In addition to shedding light on the nature of associability enhancements, our findings offer the neuroscientist a behavioral tool to dissociate their neural substrates from those of other, behavior system- or valence-specific changes. Moreover, our results present an opportunity to utilize associability enhancements to the advantage of counterconditioning procedures in therapeutic contexts. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Neural correlates of variations in event processing during learning in basolateral amygdala.

The discovery that dopamine neurons signal errors in reward prediction has demonstrated that concepts empirically derived from the study of animal behavior can be used to understand the neural implementation of reward learning. Yet the learning theory models linked to phasic dopamine activity treat attention to events such as cues and rewards as static quantities; other models, such as Pearce-Hall, propose that learning might be influenced by variations in processing of these events. A key feature of these accounts is that event processing is modulated by unsigned rather than signed reward prediction errors. Here we tested whether neural activity in rat basolateral amygdala conforms to this pattern by recording single units in a behavioral task in which rewards were unexpectedly delivered or omitted. We report that neural activity at the time of reward is providing an unsigned error signal with characteristics consistent with those postulated by these models. This neural signal increased immediately after a change in reward, and stronger firing was evident whether the value of the reward increased or decreased. Further, as predicted by these models, the change in firing developed over several trials as expectations for reward were repeatedly violated. This neural signal was correlated with faster orienting to predictive cues after changes in reward, and abolition of the signal by inactivation of basolateral amygdala disrupted this change in orienting and retarded learning in response to changes in reward. These results suggest that basolateral amygdala serves a critical function in attention for learning.

Reconciling the influence of predictiveness and uncertainty on stimulus salience: a model of attention in associative learning.

Theories of selective attention in associative learning posit that the salience of a cue will be high if the cue is the best available predictor of reinforcement (high predictiveness). In contrast, a different class of attentional theory stipulates that the salience of a cue will be high if the cue is an inaccurate predictor of reinforcement (high uncertainty). Evidence in support of these seemingly contradictory propositions has led to: (i) the development of hybrid attentional models that assume the coexistence of separate, predictiveness-driven and uncertainty-driven mechanisms of changes in cue salience; and (ii) a surge of interest in identifying the neural circuits underpinning these mechanisms. Here, we put forward a formal attentional model of learning that reconciles the roles of predictiveness and uncertainty in salience modification. The issues discussed are relevant to psychologists, behavioural neuroscientists and neuroeconomists investigating the roles of predictiveness and uncertainty in behaviour.

Changes in attention to an irrelevant cue that accompanies a negative patterning [corrected] discrimination.

Pigeons were trained in two experiments with negative patterning discriminations that were accompanied by an irrelevant cue. For Experiment 1, the discriminations were of the form AX+ BX+ ABX-, where A and B were relevant, X was irrelevant, and + or - indicate whether or not reinforcement was delivered. The discriminations for Experiment 2 were of the form A+ B+ AX+ BX+ ABX-. A subsequent test phase in both experiments revealed that the associability of A and B, and hence the attention paid to these stimuli, was less than the associability of X. The results are explained with a modified version of a configural theory of associative learning.

Agency rescues competition for credit assignment among predictive cues from adverse learning conditions.

A fundamental assumption of learning theories is that the credit assigned to predictive cues is not simply determined by their probability of reinforcement, but by their ability to compete with other cues present during learning. This assumption has guided behavioral and neural science research for decades, and tremendous empirical and theoretical advances have been made identifying the mechanisms of cue competition. However, when learning conditions are not optimal (e.g., when training is massed), cue competition is attenuated. This failure of the learning system exposes the individual's vulnerability to form spurious associations in the real world. Here, we uncover that cue competition in rats can be rescued when conditions are suboptimal provided that the individual has agency over the learning experience. Our findings reveal a new effect of agency over learning on credit assignment among predictive cues, and open new avenues of investigation into the underlying mechanisms.

All that glitters ... dissociating attention and outcome expectancy from prediction errors signals.

Initially reported in dopamine neurons, neural correlates of prediction errors have now been shown in a variety of areas, including orbitofrontal cortex, ventral striatum, and amygdala. Yet changes in neural activity to an outcome or cues that precede it can reflect other processes. We review the recent literature and show that although activity in dopamine neurons appears to signal prediction errors, similar activity in orbitofrontal cortex, basolateral amygdala, and ventral striatum does not. Instead, increased firing in basolateral amygdala to unexpected outcomes likely reflects attention, whereas activity in orbitofrontal cortex and ventral striatum is unaffected by prior expectations and may provide information on outcome expectancy. These results have important implications for how these areas interact to facilitate learning and guide behavior.

Female rats take longer than male rats to update reward expectancies when outcomes are worse than expected.

The ability to update predictive relationships and adjust behavior accordingly is critical for survival. Females take longer to update expectancies under conditions of outcome omission. It remains unknown whether that is also the case under conditions when outcomes are delivered such as in overexpectation. Here we examined whether male and female rats are able to learn from overexpectation using the same learning parameters. Our data show that males but not females learn from overexpectation when given just a single day of compound training, whereas both sexes learn when given extended 2 days of overexpectation training. These data provide important insight into sex differences that link with prior work and thus open an avenue for the study of how conflicting memories interact in the male and female brain. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Different methods of fear reduction are supported by distinct cortical substrates.

Understanding how learned fear can be reduced is at the heart of treatments for anxiety disorders. Tremendous progress has been made in this regard through extinction training in which the aversive outcome is omitted. However, current progress almost entirely rests on this single paradigm, resulting in a very specialized knowledgebase at the behavioural and neural level of analysis. Here, we used a dual-paradigm approach to show that different methods that lead to reduction in learned fear in rats are dissociated in the cortex. We report that the infralimbic cortex has a very specific role in fear reduction that depends on the omission of aversive events but not on overexpectation. The orbitofrontal cortex, a structure generally overlooked in fear, is critical for downregulating fear when novel predictions about upcoming aversive events are generated, such as when fear is inflated or overexpected, but less so when an expected aversive event is omitted.

A self-initiated cue-reward learning procedure for neural recording in rodents.

BACKGROUND: Single-unit recording in Pavlovian conditioning tasks requires the use of within-subject designs as well as sampling a considerable number of trials per trial type and session, which increases the total trial count. Pavlovian conditioning, on the other hand, requires a long average intertrial interval (ITI) relative to cue duration for cue-specific learning to occur. These requirements combined can make the session duration unfeasibly long. NEW METHOD: To circumvent this issue, we developed a self-initiated variant of the Pavlovian magazine-approach procedure in rodents. Unlike the standard procedure, where the animals passively receive the trials, the self-initiated procedure grants animals agency to self-administer and self-pace trials from a predetermined, pseudorandomized list. Critically, whereas in the standard procedure the typical ITI is in the order of minutes, our procedure uses a much shorter ITI (10 s). RESULTS: Despite such a short ITI, discrimination learning in the self-initiated procedure is comparable to that observed in the standard procedure with a typical ITI, and superior to that observed in the standard procedure with an equally short ITI. COMPARISON WITH EXISTING METHOD(S): The self-initiated procedure permits delivering 100 trials in a ∼1-h session, almost doubling the number of trials safely attainable over that period with the standard procedure. CONCLUSIONS: The self-initiated procedure enhances the collection of neural correlates of cue-reward learning while producing good discrimination performance. Other advantages for neural recording studies include ensuring that at the start of each trial the animal is engaged, attentive and in the same location within the conditioning chamber.