This Perspective will examine the organization of intrastriatal circuitry, review recent findings in this area, and discuss how the pattern of connectivity between striatal neurons might give rise to the behaviorally observed synergism between the direct/indirect pathway neurons. The emphasis of this Perspective is on the underappreciated role of lateral inhibition between striatal projection cells in controlling neuronal firing and shaping the output of this circuit. We review some classic studies in combination with more recent anatomical and functional findings to lay out a framework for an updated model of the local intra-striatal circuitry and its contribution to the formation of functional units of processing with the striatum and the integration and filtering of inputs to generate motor patterns and learned behaviors.

Learning to predict rewards based on environmental cues is essential for survival. It is believed that animals learn to predict rewards by updating predictions whenever the outcome deviates from expectations, and that such reward prediction errors (RPEs) are signaled by the mesolimbic dopamine system—a key controller of learning. However, instead of learning prospective predictions from RPEs, animals can infer predictions by learning the retrospective cause of rewards. Hence, whether mesolimbic dopamine instead conveys a causal associative signal that sometimes resembles RPE remains unknown. We developed an algorithm for retrospective causal learning and found that mesolimbic dopamine release conveys causal associations but not RPE, thereby challenging the dominant theory of reward learning. Our results reshape the conceptual and biological framework for associative learning.

Active maternal smoking has adverse effects on neurobehavioral development of the offspring, with nicotine (Nic) providing much of the underlying causative mechanism. To determine whether the lower exposures caused by second-hand smoke are deleterious, we administered tobacco smoke extract (TSE) to pregnant rats starting preconception and continued through the second postnatal week, corresponding to all 3 trimesters of fetal brain development. Dosing was adjusted to produce maternal plasma Nic concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers. We then compared TSE effects to those of an equivalent dose of Nic alone, and to a 10-fold higher Nic dose. Gestational exposure to TSE and Nic significantly disrupted cognitive and behavioral function in behavioral tests given during adolescence and adulthood (postnatal weeks 4-40), producing hyperactivity, working memory deficits, and impairments in emotional processing, even at the low exposure levels corresponding to second-hand smoke. Although TSE effects were highly correlated with those of Nic, the effects of TSE were much larger than could be attributed to just the Nic in the mixture. Indeed, TSE effects more closely resembled those of the 10-fold higher Nic levels, but still exceeded their magnitude. In combination with our earlier findings, this study thus completes the chain of causation to prove that second-hand smoke exposure causes neurodevelopmental deficits, originating in disruption of neurodifferentiation, leading to miswiring of neuronal circuits, and as shown here, culminating in behavioral dysfunction. As low level exposure to Nic alone produced neurobehavioral teratology, 'harm reduction' Nic products do not abolish the potential for neurodevelopmental damage.

The insular cortex has been associated with the processing of rewarding stimuli and with the neural bases of drug addiction. Ischemic damage to the insula has been associated with decreased desire to smoke cigarettes. Which component of insular function is involved in the neural basis of cigarette smoking is not clear. Dopamine systems are crucial for the reinforcing value of addictive drugs. The DA projection from the ventral tegmental area to the nucleus accumbens (NAc) has been shown to be a vital pathway for the primary reinforcement caused by taking a variety of abused drugs. In the current set of studies, the roles of D1 and D2 receptors in the insular cortex in the self-administration of nicotine by rats were assessed. Adult female Sprague-Dawley rats were fitted with jugular catheters and given access to self-administer nicotine. Bilateral local infusion cannulae were implanted into the agranular insular cortex to locally administer D1 and D2 antagonists (SCH-23390 and haloperidol). Acute local infusions of the D1 antagonist SCH-23390 into the insula (1–2 μg/side) significantly decreased nicotine self-administration by more than 50%. Repeated infusions of SCH-23390 into the agranular insula caused continuing decreases in nicotine self-administration without signs of tolerance. In contrast, local infusions of the D2 antagonist haloperidol 0.5–2 μg/side did not have any discernable effect on nicotine self-administration. These studies show the importance of DA D1 systems in the insula for nicotine reward.

Nicotine has been well characterized to improve memory and attention. Nicotine is the primary, but not only neuroactive compound in tobacco. Other tobacco constituents such as anabasine and anatabine also have agonist actions on nicotinic receptors. The current study investigated the effects of anabasine and anatabine on memory and attention. Adult female Sprague-Dawley rats were trained on a win-shift spatial working and reference memory task in the 16-arm radial maze or a visual signal detection operant task to test attention. Acute dose-effect functions of anabasine and anatabine over two orders of magnitude were evaluated for both tasks. In the radial-arm maze memory test, anabasine but not anatabine significantly reduced the memory impairment caused by the NMDA antagonist dizocilpine (MK-801). In the signal detection attentional task, anatabine but not anabasine significantly attenuated the attentional impairment caused by dizocilpine. These studies show that non-nicotine nicotinic agonists in tobacco, similar to nicotine, can significantly improve memory and attentional function. Both anabasine and anatabine produced cognitive improvement, but their effectiveness differed with regard to memory and attention. Follow-up studies with anabasine and anatabine are called to determine their efficacy as therapeutics for memory and attentional dysfunction.

No abstract

Nicotinic systems have been shown by a variety of studies to be involved in cognitive function. Nicotinic receptors have an inherent property to become desensitized after activation. The relative role of nicotinic receptor activation vs. net receptor inactivation by desensitization in the cognitive effects of nicotinic drugs remains to be fully understood. In these studies, we tested the effects of the α7 nicotinic receptor antagonist methyllycaconitine (MLA), the α4β2 nicotinic receptor antagonist dihydro-β-erythroidine (DHβE), the nonspecific nicotinic channel blocker mecamylamine and the α4β2 nicotinic receptor desensitizing agent sazetidine-A on learning in a repeated acquisition test. Adult female Sprague-Dawley rats were trained on a repeated acquisition learning procedure in an 8-arm radial maze. MLA (1–4 mg/kg), DHβE (1–4 mg/kg), mecamylamine (0.125–0.5 mg/kg) or sazetidine-A (1 and 3 mg/kg) were administered in four different studies either alone or together with the NMDA glutamate antagonist dizocilpine (0.05 and 0.10 mg/kg). MLA significantly counteracted the learning impairment caused by dizocilpine. The overall choice accuracy impairment caused by dizocilpine was significantly attenuated by co-administration of DHβE. Low doses of the non-specific nicotinic antagonist mecamylamine also reduced dizocilpine-induced repeated acquisition impairment. Sazetidine-A reversed the accuracy impairment caused by dizocilpine. These studies provide evidence that a net decrease in nicotinic receptor activity can improve learning by attenuating learning impairment induced by NMDA glutamate blockade. This adds to evidence in cognitive tests that nicotinic antagonists can improve cognitive function. Further research characterizing the efficacy and mechanisms underlying nicotinic antagonist and desensitization induced cognitive improvement is warranted.

How do we learn associations in the world (e.g., between cues and rewards)? Cue-reward associative learning is controlled in the brain by mesolimbic dopamine. It is widely believed that dopamine drives such learning by conveying a reward prediction error (RPE) in accordance with temporal difference reinforcement learning (TDRL) algorithms. TDRL implementations are trial-based: learning progresses sequentially across individual cue-outcome experiences. Accordingly, a foundational assumption, often considered a mere truism, is that the more cue-reward pairings one experiences, the more one learns this association. Here, we disprove this assumption, thereby falsifying a foundational principle of trial-based learning algorithms. Specifically, when a group of head-fixed mice received ten times fewer experiences over the same total time as another, a single experience produced as much learning as ten experiences in the other group. This quantitative scaling also holds for mesolimbic dopaminergic learning, with the increase in learning rate being so high that the group with fewer experiences exhibits dopaminergic learning in as few as four cue-reward experiences and behavioral learning in nine. An algorithm implementing reward-triggered retrospective learning explains these findings. The temporal scaling and few-shot learning observed here fundamentally changes our understanding of the neural algorithms of associative learning.