脑内乙酰胆碱与认知活动的关系

脑内细胞外乙酰胆碱（ACh）的变化主要反映胆碱能神经元的活动,皮层和海马等脑区的ACh主要来源于基底前脑胆碱能神经元的纤维投射。应用微透析等技术在体检测清醒、自由活动动物认知过程中脑内乙酰胆碱的含量,可以研究ACh与特定行为反应和认知活动之间的关系。研究发现当机体需要对新刺激进行分析时,在学习与记忆、空间工作记忆、注意、自发运动和探究行为等认知活动中,基底前脑胆碱能神经元被激活,脑内ACh的释放也随之改变。结果提示脑内胆碱能递质系统活动与认知过程密切相关     

Short-term estrogen treatment in ovariectomized rats augments hippocampal acetylcholine release during place learning

Estrogen modulates learning and memory in ovariectomized and naturally cycling female rats, especially in tasks using spatial learning and navigation. Estrogen also modulates cholinergic function in various forebrain structures. Past studies have shown positive correlations between hippocampal ACh output and performance on hippocampus-dependent tasks. The present study examined whether estradiol replacement would potentiate hippocampal ACh release during place learning. In vivo microdialysis and HPLC were used to measure extracellular ACh levels in the hippocampus of ovariectomized female rats that had received s.c. injections of 17beta-estradiol (10 microg) or sesame oil (vehicle treatment) 48 and 24h prior to training on a place task. Estrogen did not alter baseline levels of extracellular ACh in the hippocampus. During training, hippocampal ACh increased in ovariectomized rats regardless of estrogen status. However, while estradiol did not enhance learning in this experiment, estradiol significantly potentiated the increase in hippocampal ACh release seen during place training. This represents the first demonstration of on-line assessment of ACh output in hippocampus during learning in female rats and suggests that estrogen-dependent modulation of ACh release during training might control activation of different neural systems used during learning.     

Acetylcholine modulation of neural systems involved in learning and memory

Extensive evidence supports the view that cholinergic mechanisms modulate learning and memory formation. This paper reviews evidence for cholinergic regulation of multiple memory systems, noting that manipulations of cholinergic functions in many neural systems can enhance or impair memory for tasks generally associated with those neural systems. While parallel memory systems can be identified by combining lesions with carefully crafted tasks, most—if not all—tasks require the combinatorial participation of multiple neural systems. This paper offers the hypothesis that the magnitude of acetylcholine (ACh) release in different neural systems may regulate the relative contributions of these systems to learning. Recent studies of ACh release, obtained with in vivo microdialysis samples during training, together with direct injections of cholinergic drugs into different neural systems, provide evidence that release of ACh is important in engaging these systems during learning, and that the extent to which the systems are engaged is associated with individual differences in learning and memory.     

Differential acetylcholine release in the prefrontal cortex and hippocampus during pavlovian trace and delay conditioning

Pavlovian trace conditioning critically depends on the medial prefrontal cortex (mPFC) and hippocampus (HPC), whereas delay conditioning does not depend on these brain structures. Given that the cholinergic basal forebrain system modulates activity in both the mPFC and HPC, it was reasoned that the level of acetylcholine (ACh) release in these regions would show distinct profiles during testing in trace and delay conditioning paradigms. To test this assumption, microdialysis probes were implanted unilaterally into the mPFC and HPC of rats that were pre-trained in appetitive trace and delay conditioning paradigms using different conditional stimuli in the two tasks. On the day of microdialysis testing, dialysate samples were collected during a quiet baseline interval before trials were initiated, and again during performance in separate blocks of trace and delay conditioning trials in each animal. ACh levels were quantified using high-performance liquid chromatography and electrochemical detection techniques. Consistent with our hypothesis, results showed that ACh release in the mPFC was greater during trace conditioning than during delay conditioning. The level of ACh released during trace conditioning in the HPC was also greater than the levels observed during delay conditioning. While ACh efflux in both the mPFC and HPC selectively increased during trace conditioning, ACh levels in the mPFC during trace conditioning testing showed the greatest increases observed. These results demonstrate a dissociation in cholinergic activation of the mPFC and HPC during performance in trace but not delay appetitive conditioning, where this cholinergic activity may contribute to attentional mechanisms, adaptive response timing, or memory consolidation necessary for successful trace conditioning.     

Septohippocampal acetylcholine: involved in but not necessary for learning and memory?

The neurotransmitter acetylcholine (ACh) has been accorded an important role in supporting learning and memory processes in the hippocampus. Cholinergic activity in the hippocampus is correlated with memory, and restoration of ACh in the hippocampus after disruption of the septohippocampal pathway is sufficient to rescue memory. However, selective ablation of cholinergic septohippocampal projections is largely without effect on hippocampal-dependent learning and memory processes. We consider the evidence underlying each of these statements, and the contradictions they pose for understanding the functional role of hippocampal ACh in memory. We suggest that although hippocampal ACh is involved in memory in the intact brain, it is not necessary for many aspects of hippocampal memory function.     

胚胎期可卡因、吗啡暴露影响子代成瘾相关行为的神经发育机制

孕期使用毒品可影响胎儿大脑的正常发育,导致脑内神经递质系统异常以及行为的改变.近年来不断有研究证据提示,胚胎期接触可卡因、吗啡等成瘾药物,可以影响神经细胞的增殖、迁移或凋亡等发育过程,使中脑皮层边缘系统中多巴胺、GABA、谷氨酸等神经元形态、受体功能以及突触可塑性发生改变,从而导致子代的学习记忆和成瘾易感性等行为异常.本文将从行为、神经发育、递质系统以及脑功能等层面归纳胚胎期用药对成瘾相关行为影响机制的重要研究进展,并试图提出可能的研究展望.     

ENSEMBLE RECORDINGS IN AWAKE RATS: ACHIEVING BEHAVIORAL REGULARITY DURING MULTIMODAL STIMULUS PROCESSING AND DISCRIMINATIVE LEARNING

To meet an increasing need to examine the neurophysiological underpinnings of behavior in rats, we developed a behavioral system for studying sensory processing, attention and discrimination learning in rats while recording firing patterns of neurons in one or more brain areas of interest. Because neuronal activity is sensitive to variations in behavior which may confound the identification of neural correlates, a specific aim of the study was to allow rats to sample sensory stimuli under conditions of strong behavioral regularity. Our behavioral system allows multimodal stimulus presentation and is coupled to modules for delivering reinforcement, simultaneous monitoring of behavior and recording of ensembles of well isolated single neurons. Using training protocols for simple and compound discrimination, we validated the behavioral system with a group of 4 rats. Within these tasks, a majority of medial prefrontal neurons showed significant firing‐rate changes correlated to one or more trial events that could not be explained from significant variation in head position. Thus, ensemble recordings can be combined with discriminative learning tasks under conditions of strong behavioral regularity.     

Muscarinic cholinergic influences in memory consolidation

The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. Although mR activation is no doubt involved in many aspects of cognitive functioning, the extensive evidence that memory is influenced by cholinergic treatments given after training either systemically or intra-cranially clearly indicates that cholinergic activation via mRs is a critical component in modulation of memory consolidation. Furthermore, the evidence indicates that activation of mRs in the basolateral amygdala (BLA) plays an essential role in enabling other neuromodulatory influences on memory consolidation. Memory can also be affected by posttraining activation of mRs in the hippocampus, striatum and cortex. Evidence of increases in hippocampal and cortical acetylcholine (ACh) levels following learning experiences support the view that endogenous ACh release is involved in long-term memory consolidation. Furthermore, the findings indicating that mR drug treatments influence plasticity in the hippocampus and in sensory cortices strongly suggest that mR activation is involved in the storage of information in these brain regions.     

The NK3 receptor agonist senktide ameliorates scopolamine-induced deficits in memory for object, place and temporal order

Senktide, a potent neurokinin-3 receptor (NK₃-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schäble et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK₃-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK₃-R agonists and their activating influence on ACh suggest a possible role of the NK₃-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK₃-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous – s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object–place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object–place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine-induced memory impairments and indicate that the promnestic action of NK₃-R agonists is mediated by muscarinic cholinergic mechanisms.     

Nucleus basalis magnocellularis and memory: differential effects of two neurotoxins

Although the cholinergic system is involved in memory, noncholinergic systems may also contribute to memory. Lesions of the nucleus basalis magnocellularis (NBM) produce behavioral impairments and reduction of cholinergic markers in the frontal cortex (FC). The present study compared the behavioral effects of lesions made with two different neurotoxins, ibotenic (IBO) acid and quisqualic (QUIS) acid. IBO or QUIS was injected into the NBM, and rats were tested in three different tasks: cued delayed nonmatch-to-sample (CDNMS), spatial delayed nonmatch-to-sample (SDNMS), and spatial two-choice simultaneous discrimination (STCSD). IBO producted a greater behavioral impairment than QUIS in the CDNMS and the SDNMS, although QUIS produced a greater drop in choline acetyltransferase (ChAT) activity in the cortex than IBO. At the end of behavioral testing, IBO rats, but not QUIS rats, were impaired in the retention of both tasks. The fact that QUIS lesions produced a greater loss of NBM cholinergic neurons, as determined by decreased ChAT activity, but less of a behavioral impairment in both a spatial and nonspatial task, suggests that the loss of noncholinergic NBM neurons must contribute to the memory impairments following NBM cell loss.     

The putative role of free radicals in the loss of neuronal functioning in senescence.

One of the hallmarks of the aging process is a loss of sensitivity in central neuronal receptors to agonist stimulation. This appears to be especially true in central (hippocampal, striatal) muscarinic cholinergic systems and in the striatal dopamine systems. For these two systems, any decline in their sensitivity can be of extreme importance in determining the behavioral capabilities of the organism. Decrements in the striatal dopamine system may be reflected as motor behavioral deficits, while the central cholinergic systems play a major role in the processing of memory through the activation of muscarinic receptors (mAChR). Declines in the function of these receptors appear to be at least partially responsible for the marked deterioration of cognitive function in normal aging and, more notably, in Alzheimer's disease (AD). Previous work has indicated only minimal success in improving performance in tasks that assess memory in senescent animals or humans with pharmacological agents which enhance cholinergic functioning. The present review describes research that indicates that two of the factors involved in this decline in receptor sensitivity include: (a) decreased receptor concentrations and (b) age-related decrements in signal transduction pathways. Studies are reviewed that indicate that the oxidative neural damage that occurs via kainic acid or ionizing radiation parallel those seen in aging. It is suggested that the common mechanism that may exist among all of the age-, disease-, excitatory amino acid- or radiation-induced deficits in neuronal transmission may involve free-radical-mediated alterations in membrane integrity through lipid peroxidation.     

The putative role of free radicals in the loss of neuronal functioning in senescence

One of the hallmarks of the aging process is a loss of sensitivity in central neuronal receptors to agonist stimulation. This appears to be especially true in central (hippocampal, striatal) muscarinic cholinergic systems and in the striatal dopamine systems. For these two systems, any decline in their sensitivity can be of extreme importance in determining the behavioral capabilities of the organism. Decrements in the striatal dopamine system may be reflected as motor behavioral deficits, while the central cholinergic systems play a major role in the processing of memory through the activation of muscarinic receptors (mAChR). Declines in the function of these receptors appear to be at least partially responsible for the marked deterioration of cognitive function in normal aging and, more notably, in Alzheimer’s disease (AD). Previous work has indicated only minimal success in improving performance in tasks that assess memory in senescent animals or humans with pharmacological agents which enhance cholinergic functioning. The present review describes research that indicates that two of the factors involved in this decline in receptor sensitivity include: (a) decreased receptor concentrations and (b) age-related decrements in signal transduction pathways. Studies are reviewed that indicate that the oxidative neural damage that occurs via kainic acid or ionizing radiation parallel those seen in aging. It is suggested that the common mechanism that may exist among all of the age-, disease-, excitatory amino acid- or radiation-induced deficits in neuronal transmission may involve free-radical-mediated alterations in membrane integrity through lipid peroxidation.     

Associative representational plasticity in the auditory cortex: a synthesis of two disciplines

Historically, sensory systems have been largely ignored as potential loci of information storage in the neurobiology of learning and memory. They continued to be relegated to the role of "sensory analyzers" despite consistent findings of associatively induced enhancement of responses in primary sensory cortices to behaviorally important signal stimuli, such as conditioned stimuli (CS), during classical conditioning. This disregard may have been promoted by the fact that the brain was interrogated using only one or two stimuli, e.g., a CS(+) sometimes with a CS(-), providing little insight into the specificity of neural plasticity. This review describes a novel approach that synthesizes the basic experimental designs of the experimental psychology of learning with that of sensory neurophysiology. By probing the brain with a large stimulus set before and after learning, this unified method has revealed that associative processes produce highly specific changes in the receptive fields of cells in the primary auditory cortex (A1). This associative representational plasticity (ARP) selectively facilitates responses to tonal CSs at the expense of other frequencies, producing tuning shifts toward and to the CS and expanded representation of CS frequencies in the tonotopic map of A1. ARPs have the major characteristics of associative memory: They are highly specific, discriminative, rapidly acquired, exhibit consolidation over hours and days, and can be retained indefinitely. Evidence to date suggests that ARPs encode the level of acquired behavioral importance of stimuli. The nucleus basalis cholinergic system is sufficient both for the induction of ARPs and the induction of specific auditory memory. Investigation of ARPs has attracted workers with diverse backgrounds, often resulting in behavioral approaches that yield data that are difficult to interpret. The advantages of studying associative representational plasticity are emphasized, as is the need for greater behavioral sophistication.     

Anterior thalamic lesions alter both hippocampal-dependent behavior and hippocampal acetylcholine release in the rat

The anterior thalamic nuclei (ATN) are important for learning and memory as damage to this region produces a persistent amnestic syndrome. Dense connections between the ATN and the hippocampus exist, and importantly, damage to the ATN can impair hippocampal functioning. Acetylcholine (ACh) is a key neurotransmitter in the hippocampus, and in vivo measures of ACh are correlated to learning and memory performance. In the present study, complete lesions of the ATN impaired performance on two measures of hippocampal-dependent learning and memory (spontaneous alternation and delayed alternation) and severely disrupted behaviorally evoked ACh efflux within the hippocampus of adult male rats. In contrast, incomplete ATN lesions did not impair spontaneous alternation performance but did impair delayed alternation performance while blunting hippocampal ACh efflux. Interestingly, ATN lesions of any size did not affect basal concentrations of ACh in the hippocampus. These results demonstrate that the ATN have the capacity to modulate behaviorally relevant neuronal transmission within the hippocampus.     

Motivationally neutral stimulation of the nucleus basalis induces specific behavioral memory

The cholinergic system has been implicated in learning and memory. The nucleus basalis (NB) provides acetylcholine (ACh) to the cerebral cortex. Pairing a tone with NB stimulation (NBstm) to alter cortical state induces both associative specific tuning plasticity in the primary auditory cortex (A1) and associative specific auditory behavioral memory. NB-induced memory has major features of natural memory that is induced by pairing a tone with motivational reinforcers, e.g., food or shock, suggesting that the cholinergic system may be a “final common pathway” whose activation promotes memory storage. Alternatively, NB stimulation might itself be motivationally significant, either rewarding or punishing. To investigate these alternatives, adult male rats (n = 7) first formed a specific NB-induced memory (CS = 8.0 kHz, 2.0 s paired with NBstm, ISI = 1.8 s, 200 trials), validated by post-training (24 h) frequency generalization gradients (1–15 kHz) of respiration interruption that were specific to the CS frequency. Thereafter, they received the same level of NBstm that had induced memory, while confined to one quadrant of an arena, and later tested for place-preference, i.e., avoidance or seeking of the quadrant of NBstm. This NBstm group exhibited neither preference for nor against the stimulated quadrant, compared to sham-operated subjects (n = 7). The findings indicate that specific associative memory can be induced by direct activation of the NB without detectable motivational effects of NB stimulation. These results are concordant with a memory-promoting role for the nucleus basalis that places it “downstream” of motivational systems, which activate it to initiate the storage of the current state of its cholinergic targets.     

In Vivo Hippocampal Acetylcholine Release During Exposure to Acute Stress

Hippocampal extracellular acetylcholine (ACh) and choline levels were evaluated using in vivo microdialysis in male Fischer 344 rats before, during, and following an 80-min exposure to two different stress conditions. Measurements were taken in rats restrained and immersed in a water bath containing either 37 degreesC (normothermic-restraint) or 20 degreesC (cold-restraint) water. Results were compared to normothermic-freely-moving rats. Cold-restrained rats displayed decreased ACh levels during cold exposure relative to both normothermic-restrained and normothermic-freely-moving rats. By the end of the cold exposure period and following removal from cold, ACh levels had returned to near-baseline values. Normothermic-restrained rats had levels similar to those of normothermic-freely-moving rats, except for a marked increase in ACh following removal from restraint. Cold-restrained rats displayed a gradual elevation in choline levels during cold stress, followed by a gradual decline after stress termination, whereas both normothermic-restrained and normothermic-freely-moving rats displayed gradual decreases during the microdialysis session. These findings demonstrate that central cholinergic neurotransmission can be altered by the application of, and removal from, acute stressors. In addition, the results suggest a possible relationship between the magnitudes of both the stressor and its cholinergic consequences.     

Acetylcholine release in the hippocampus and prelimbic cortex during acquisition of a socially transmitted food preference

Interference with cholinergic functions in hippocampus and prefrontal cortex impairs learning and memory for social transmission of food preference, suggesting that acetylcholine (ACh) release in the two brain regions may be important for acquiring the food preference. This experiment examined release of ACh in the hippocampus and prefrontal cortex of rats during training for social transmission of food preference. After demonstrator rats ate a food with novel flavor and odor, a social transmission of food preference group of rats was allowed to interact with the demonstrators for 30 min, while in vivo microdialysis collected samples for later measurement of ACh release with HPLC methods. A social control group observed a demonstrator that had eaten food without novel flavor and odor. An odor control group was allowed to smell but not ingest food with novel odor. Rats in the social transmission but not control groups preferred the novel food on a trial 48 h later. ACh release in prefrontal cortex, with probes that primarily sampled prelimbic cortex, did not increase during acquisition of the social transmission of food preference, suggesting that training-initiated release of ACh in prelimbic cortex is not necessary for acquisition of the food preference. In contrast, ACh release in the hippocampus increased substantially (200%) upon exposure to a rat that had eaten the novel food. Release in the hippocampus increased significantly less (25%) upon exposure to a rat that had eaten normal food and did not increase significantly in the rats exposed to the novel odor; ACh release in the social transmission group was significantly greater than that of the either of the control groups. Thus, ACh release in the hippocampus but not prelimbic cortex distinguished well the social transmission vs. control conditions, suggesting that cholinergic mechanisms in the hippocampus but not prelimbic cortex are important for acquiring a socially transmitted food preference.     

Neural representations during sleep: from sensory processing to memory traces

In the course of a day, the brain undergoes large-scale changes in functional modes, from attentive wakefulness to the deepest stage of sleep. The present paper evaluates how these state changes affect the neural bases of sensory and cognitive representations. Are organized neural representations still maintained during sleep? In other words, despite the absence of conscious awareness, do neuronal signals emitted during sleep contain information and have a functional relevance? Through a critical evaluation of the animal and human literature, neural representations at different levels of integration (from the most elementary sensory level to the most cognitive one) are reviewed. Recordings of neuronal activity in animals at presentation of neutral or significant stimuli show that some analysis of the external word remains possible during sleep, allowing recognition of behaviorally relevant stimuli. Event-related brain potentials in humans confirm the preservation of some sensory integration and discriminative capacity. Behavioral and neuroimaging studies in humans substantiate the notion that memory representations are reactivated and are reorganized during post-learning sleep; these reorganisations may account for the beneficial effects of sleep on behavioral performance. Electrophysiological results showing replay of neuronal sequences in animals are presented, and their relevance as neuronal correlates of memory reactivation is discussed. The reviewed literature provides converging evidence that structured neural representations can be activated during sleep. Which reorganizations unique to sleep benefit memory representations, and to what extent the operations still efficient in processing environmental information during sleep are similar to those underlying the non-conscious, automatic processing continually at work in wakefulness, are challenging questions open to investigation.     

Specific auditory memory induced by nucleus basalis stimulation depends on intrinsic acetylcholine

Although the cholinergic system has long been implicated in the formation of memory, there had been no direct demonstration that activation of this system can actually induce specific behavioral memory. We have evaluated the "cholinergic-memory" hypothesis by pairing a tone with stimulation of the nucleus basalis (NB), which provides acetylcholine to the cerebral cortex. We found that such pairing induces behaviorally-validated auditory memory. NB-induced memory has the key features of natural memory: it is associative, highly-specific and rapidly induced. Moreover, the level of NB stimulation controls the amount of detail in memory about the tonal conditioned stimulus. While consistent with the hypothesis that properly-timed release of acetylcholine (ACh) during natural learning is sufficient to induce memory, pharmacological evidence has been lacking. This study asked whether scopolamine, a muscarinic antagonist, impairs or prevents the formation of NB-induced memory. Adult male rats were first tested for responses (disruption of ongoing respiration) to tones (1-15 kHz), constituting a pre-training behavioral frequency generalization gradient (BFGG). Then, they received a single session of 200 trials of a tone (8.00 kHz, 70 dB, 2 s) paired with electrical stimulation of the NB (100 Hz, 0.2 s). Immediately after training, they received either scopolamine (1.0 mg/kg, i.p.) or saline. Twenty-four hours later, they were tested for specific memory by obtaining post-training BFGGs. The saline group developed CS-specific memory, manifested by maximum increase in response specific to the CS frequency band. In contrast, the scopolamine group exhibited no such memory. These findings indicate that NB-induced specific associative behavioral memory requires the action of intrinsic acetylcholine at muscarinic receptors, and supports the hypothesis that natural memory formation engages the nucleus basalis and muscarinic receptors.     

Where perception meets memory: A review of repetition priming in visual search tasks

What we have recently seen and attended to strongly influences how we subsequently allocate visual attention. A clear example is how repeated presentation of an object’s features or location in visual search tasks facilitates subsequent detection or identification of that item, a phenomenon known as priming. Here, we review a large body of results from priming studies that suggest that a short-term implicit memory system guides our attention to recently viewed items. The nature of this memory system and the processing level at which visual priming occurs are still debated. Priming might be due to activity modulations of low-level areas coding simple stimulus characteristics or to higher level episodic memory representations of whole objects or visual scenes. Indeed, recent evidence indicates that only minor changes to the stimuli used in priming studies may alter the processing level at which priming occurs. We also review recent behavioral, neuropsychological, and neurophysiological evidence that indicates that the priming patterns are reflected in activity modulations at multiple sites along the visual pathways. We furthermore suggest that studies of priming in visual search may potentially shed important light on the nature of cortical visual representations. Our conclusion is that priming occurs at many different levels of the perceptual hierarchy, reflecting activity modulations ranging from lower to higher levels, depending on the stimulus, task, and context—in fact, the neural loci that are involved in the analysis of the stimuli for which priming effects are seen.