Neurobiology of Learning and Memory最新文献

Humans and animals use information about future access to rewards to influence their behaviour in the present, however the evidence for this is largely anecdotal. Here we use the nicotine intravenous self-administration paradigm to ask whether rats can use an auditory stimulus signalling a long (450 s) signalled time-out on the next trial to influence their nicotine intake in the present. Rats were trained to choose between low (15 µg/kg/infusion), medium (30 µg/kg/infusion) or high (60 µg/kg/infusion) doses of nicotine on any given trial. Trials either had a 'light' trial with no tone and a standard 20 s post-infusion time-out, a 'short-tone' trial where a tone was presented but the time-out remained at 20 s, or a 'long-tone' trial where a second tone played and was accompanied by a long 450 s time-out period. During training rats clearly showed that dose selection was based on both the dose on the previous trial and the latency between infusions. When tones were presented, rats shifted their preference from the low dose to the high dose when the long-delay tone was presented, and this choice was particularly pronounced when the rat had previously selected a low dose. Together these findings are the first evidence that rats can regulate their nicotine intake in the present in anticipation of a future non-drug period. This result is discussed with respect to theories of negative reinforcement.

Early life adversity (ELA) is associated with a multitude of neural and behavioral aberrations. To develop treatments to mitigate the effects of ELA, it is critical to determine which aspects of cognition are affected and when these disturbances manifest across the lifespan. Here, we tested the effects of maternal separation, an established rodent model of ELA, on punishment-driven risky decision-making longitudinally in both adolescence (25-55 days old) and adulthood (80-100 days old). Risk-taking was assessed with the Risky Decision-making Task, wherein rats choose between a small, safe reward and a large reward accompanied by an escalating risk of punishment (foot shock). We observed that rats exposed to maternal separation were more prone to risk-taking than controls during adolescence, and demonstrated reduced latency to make both risky and safe decisions. Interestingly, this augmented risk-taking was no longer evident in adulthood. Males and females displayed comparable levels of risk-taking during adolescence then diverged in adulthood, with adult males displaying a sharp increase in risk-taking. Finally, we observed that risk-taking changed across the lifespan in rats exposed to maternal separation, but not in control rats. Collectively, these data reveal that ELA engenders risk-taking in adolescence but not adulthood, and that sex differences in risky decision-making are not evident until adulthood. This has important implications for the development of both behavioral and biological treatments to improve decision-making during the vulnerable adolescent period.

Episodic memory is subserved by interactions between entorhinal cortex (EC) and hippocampus. Within EC, a functional dissociation has been proposed for medial (MEC) and lateral (LEC) subregions, whereby, MEC processes spatial information while LEC processes information about objects and their location in space. Most of these studies, however, used classical methods which lack both spatial and temporal specificity, thus, the precise role of MEC/LEC in memory could use further clarification. First, we show a possible functional dissociation of MEC/LEC for place/object fear memory, by optogenetic suppression of these areas during memory acquisition. The main output of EC is to the hippocampus. MEC projects mainly towards proximal/superficial CA1 and deep CA3 while LEC towards distal/deep CA1 and superficial CA3. Dentate gyrus (DG), terminations of MEC/LEC are dissociated septotemporally. A functional dissociation has also been proposed for subregions of the hippocampus. Previous studies reported that proximal/distal CA1 process spatial/nonspatial information, respectively. For the second part of the study, we used the immediate-early gene Zif-268 to map neuronal activity in CA1. We first show enhanced Zif-268 expression and cluster-type organization in the proximal CA1 by place exposure and enhanced Zif-268 expression/cluster organization in distal CA1 following object exposure. Second, direct optogenetic stimulation of MEC/LEC, produced a similar enhancement/cluster-type organization in the same areas. Enhanced Zif-268 expression was also observed in CA3 and DG. These results substantiate previous findings and are proof positive that the hippocampus is organized in clusters to encode information generally ascribed to this structure.

The ability to choose between options that differ in their risks and rewards depends on brain regions within the mesocorticolimbic circuit and regulation of their activity by neurotransmitter systems. Dopamine neurotransmission in particular plays a critical role in modulating such risk-taking behavior; however, the contribution of other major modulatory neurotransmitters, such as acetylcholine, is not as well-defined, especially for decision making in which the risk associated with more rewarding outcomes involves adverse consequences. Consequently, the goal of the current experiments was to examine how cholinergic signaling influences decision making involving risk of explicit punishment. Male and female rats were trained in a decision-making task in which they chose between a small safe food reward and a larger food reward accompanied by a risk of footshock punishment. After training in this task, the effects of nicotinic and muscarinic agonists and antagonists on risk-taking performance were evaluated. Neither nicotine, a nicotinic receptor agonist, nor mecamylamine, a nicotinic receptor antagonist, affected preference for the risky lever, although mecamylamine did alter latencies to press the risky lever and the percentage of omissions. The muscarinic receptor agonist oxotremorine decreased preference for the large, risky lever; similar effects on behavior were observed with the administration of the muscarinic receptor antagonist scopolamine. Control experiments were therefore conducted in which these same muscarinic receptor ligands were administered prior to testing in a reward discrimination task. These experiments revealed that the effects of oxotremorine and scopolamine on risk taking may be due to altered motivational processes rather than to changes in sensitivity to risk of punishment. Importantly, there were no sex differences in the effects of cholinergic manipulations on preference for the large, risky lever. Collectively, these findings suggest that in both males and females, cholinergic signaling via muscarinic receptors is involved in decision making involving risk of explicit punishment, with a specific role in modulating sensitivity to differences in reward magnitude. Future studies will expand upon this work by exploring whether targeting cholinergic receptors has therapeutic potential for psychiatric conditions in which risk taking is pathologically altered.

Consolidated long-term memories can undergo strength or content modification via protein synthesis-dependent reconsolidation. This is the process by which a reminder cue initiates reactivation of the memory trace, triggering destabilization. Older and more strongly encoded spatial memories can resist destabilization due to biological boundary conditions. The present study investigated the role of dopamine (DA) at D1 receptors (D1Rs) in object location memory destabilization and overcoming boundary conditions for older ("remote"; tested with a 48-h rather than a 24-h delay between sample and reactivation) memory destabilization. Using male rats in a modified object location task, we found that administering the D1R antagonist SCH23390 (0.1 mg/kg, i.p.) prior to reactivation blocked destabilization of recently encoded memories, as well as novelty-induced destabilization of remote memories. Using remote parameters, systemically administered D1R agonist SKF38393 (5 mg/kg, i.p.) induced destabilization of remote object location memories in the absence of salient novelty. Intra-dorsal hippocampus administration of SCH23390 (2 μg/μL) also blocked destabilization of remote object location memories when a salient novel cue was present. These results are consistent with previous findings implicating DA in memory destabilization as well as demonstrate a role for D1-receptor activation in the destabilization of boundary condition protected-object location memories.

Social learning, learning from other individuals, has been demonstrated in many animals, including insects, but its detailed neural mechanisms remain virtually unknown. We showed that crickets (Gryllus bimaculatus) exhibit aversive social learning with a dead conspecific. When a learner cricket was trained to observe a dead cricket on a drinking apparatus, the learner avoided the odor of that apparatus thereafter. Here we investigated the hypothesis that this social learning is achieved by first-order Pavlovian conditioning of an odor (conditioned stimulus) and a dead conspecific (unconditioned stimulus, US). Injection of a dopamine receptor antagonist (flupentixol) before training or testing impaired the learning or execution of the response to the learned odor, as we reported in aversive non-social Pavlovian conditioning in crickets. Moreover, crickets that were trained with a dead conspecific and then received revaluation of the dead conspecific by pairing it with water reward exhibited an appetitive conditioned response (CR) to the odor paired with the dead conspecific. This suggests that execution of the CR is governed by the current value of the US as in non-social Pavlovian conditioning. In addition, we previously suggested that appetitive social learning with a living conspecific is based on second-order conditioning (SOC), and here we showed that SOC is achieved when crickets experienced pairing of a dead conspecific with water reward before experiencing social learning training with a dead conspecific. We conclude that social learning with a dead conspecific is based on Pavlovian conditioning and that this learning can be extended to second-order social learning.