No abstract

The nucleus basalis (NB) has been implicated in memory formation indirectly, by lesions, pharmacological manipulations, and neural correlates of learning. Prior findings imply that engagement of the NB during learning promotes memory storage. We directly tested this NB-memory hypothesis by determining whether stimulation of the NB induces behavioral associative memory. Rats were trained either with paired tone (6 kHz) and NB stimulation or with the two stimuli unpaired. We later determined the specificity of cardiac and respiratory behavioral responses to the training tone and several other acoustic frequencies. Paired subjects exhibited frequency generalization gradients with a peak of 6 kHz for both cardiac and respiratory behavior. Unpaired subjects exhibited no generalization gradient. The development of such specific, associative behavioral responses indicates that tone paired with NB stimulation induced behavioral associative memory. The discovery of memory induction by direct activation of the NB supports the NB-memory hypothesis and provides a potentially powerful way to control and investigate neural mechanisms of memory.T he capacity to remember provides the fundamental ability to benefit from experience, by bridging the gap over minutes to years between transient sensory events and subsequent adaptive behavior. Although the storage of experience is undoubtedly a property of many brain systems, the cerebral cortex has drawn special attention for several reasons, including its dominant size and critical role in human cognition and behavior. However, the mechanisms underlying the storage of information in the cerebral cortex are not well understood. Although sensory receptors receive continual environmental stimulation, only a fraction of sensory events enter into memory, suggesting that other, nonsensory brain systems selectively modulate the cortex to enable the storage of experiences that are behaviorally important. Pharmacological evidence indicates that the cholinergic system is one of several neuromodulatory systems that may be directly involved in memory processes (reviewed in ref. 1). Also, many noncholinergic treatments that facilitate memory, such as adrenergic agents and stress hormones, affect memory by means of cholinergic actions (2).The nucleus basalis (NB) is a candidate for such modulatory functions because it is the major source of cortical acetylcholine (ACh) (3, 4). Stimulation of the NB increases the release of cortical ACh and produces electroencephalographic (EEG) activation (''desynchronization'') (5-7), which is the waking state affiliated with learning (8). Conversely, NB lesions reduce cortical ACh and impair cortical activation (9-11). NB cells respond increasingly to behaviorally significant stimuli during learning (12-15), and ACh is preferentially released in relevant sensory cortical areas at the time of learning (16, 17). Additionally, NB neurons projecting to the primary auditory cortex (ACx) selectively increase transcription of the gene for the synthetic enzyme of ACh,...

Learning involves not only the establishment of memory per se, but also the specific details of its contents. In classical conditioning, the former concerns whether an association was learned while the latter discloses what was learned. The neural bases of associativity have been studied extensively while neural mechanisms of memory specificity have been neglected. Stimulation of the cholinergic nucleus basalis (NBs) paired with a preceding tone induces CS-specific associative memory. As different levels of acetylcholine may be released naturally during different learning situations, we asked whether the level of activation of the cholinergic neuromodulatory system can control the degree of detail that is encoded and retrieved. Adult male rats were tested pre-and post-training for behavioral responses (interruption of ongoing respiration) to tones of various frequencies (1-15 kHz, 70 dB, 2 s). Training consisted of 200 trials/day of tone (8.0 kHz, 70 dB, 2 s) either paired or unpaired with NBs (CS-NBs = 1.8 s) at moderate (65.7 ± 9.0 μA, one day) or weak (46.7 ± 12.1 μA, three training days) levels of stimulation, under conditions of controlled behavioral state (pre-trial stable respiration rate). Post-training (24 h) responses to tones revealed that moderate activation induced both associative and CS-specific behavioral memory, whereas weak activation produced associative memory lacking frequency specificity. The degree of memory specificity 24 h after training was positively correlated with the magnitude of CS-elicited increase in γ activity within the EEG during training, but only in the moderate NBs group. Thus, a low level of acetylcholine released by the nucleus basalis during learning is sufficient to induce associativity whereas a higher level of release enables the storage of greater experiential detail. γ waves, which are thought to reflect the coordinated activity of cortical cells, appear to index the encoding of CS detail. The findings demonstrate that the amount of detail in memory can be directly controlled by neural intervention.

Hypothesized circuitry enabling behavioral memory formation can be tested by its direct activation in the absence of normal experience. Neuromodulation via the cortical release of acetylcholine by the nucleus basalis (NB) is hypothesized to be sufficient to induce specific, associative behavioral memory. Previously, we found that tone paired with stimulation of the nucleus basalis (NBs) for 3000 trials over 15 days induced such memory, supporting the hypothesis. However, as standard associative memory can be established much more rapidly, we asked whether NB-induced memory develops rapidly. Adult male Sprague-Dawley rats, trained and tested in the same calm, waking state, were divided into Paired (n=5) and control (n=4) groups, each of which received a single session of 200 trials of an 8.0 kHz conditioned stimulus (CS) either paired with NBs or with unpaired presentation of NBs. Respiration, cardiac activity, and evoked potentials in the primary auditory cortex (ACx) were recorded. Memory and its degree of specificity were assessed 24 h later by presenting tones of various frequencies (1-15 kHz) in the absence of NBs to yield behavioral frequency generalization gradients. Behavioral responses to test tones consisted of interruption of ongoing respiration and changes in heart rate. Post-training behavioral generalization gradients exhibited response peaks centered on the CS frequency for the Paired group alone. Tone evoked potentials from the ACx also developed CS-specific plasticity. The findings indicate that NB induction of specific behavioral associative memory, like normal memory, can develop rapidly and is accompanied by specific cortical plasticity, supporting the view that NB engagement during normal learning produces memory.

Receptive field (RF) plasticity in primary auditory cortex of adult animals, specifically selective increased response to a tonal conditioned stimulus (CS) relative to other frequencies, can be induced both by behavioral conditioning and by pairing a tone with stimulation of the nucleus basalis (NB). This study determined whether cortical muscarinic receptors are necessary for NB-induced RF plasticity. Single units in layers II-IV were studied in Urethane anesthetized adult rats. The cortex was perfused with saline or saline+atropine sulfate. Conditioning, 30 trials of pairing a tone with NB stimulation, produced a significant CS-specific response increase (n=8). Local atropine blocked NB-induced RF plasticity, actually resulting in CS-specific response decrease (n=6). Therefore, NB-induced RF plasticity requires engagement of muscarinic receptors in auditory cortex.