RESUMO
Trace eyeblink conditioning (TEBC) has been widely used to study associative learning in both animals and humans. In this paradigm, conditioned responses (CRs) to conditioned stimuli (CS) serve as a measure for retrieving learned associations between the CS and the unconditioned stimuli (US) within a trial. Memory consolidation, that is, learning over time, can be quantified as an increase in the proportion of CRs across training sessions. However, how hippocampal oscillations differentiate between successful memory retrieval within a session and consolidation across TEBC training sessions remains unknown. To address this question, we recorded local field potentials (LFPs) from the rat dorsal hippocampus during TEBC and investigated hippocampal oscillation dynamics associated with these two functions. We show that transient broadband responses to the CS were correlated with memory consolidation, as indexed by an increase in CRs across TEBC sessions. In contrast, induced alpha (8-10â Hz) and beta (16-20â Hz) band responses were correlated with the successful retrieval of the CS-US association within a session, as indexed by the difference in trials with and without CR.
Assuntos
Condicionamento Palpebral , Hipocampo , Consolidação da Memória , Rememoração Mental , Ratos Long-Evans , Hipocampo/fisiologia , Masculino , Condicionamento Palpebral/fisiologia , Animais , Consolidação da Memória/fisiologia , Rememoração Mental/fisiologia , Aprendizagem por Associação/fisiologia , Ratos , Condicionamento Clássico/fisiologia , Piscadela/fisiologiaRESUMO
According to the motor learning theory by Albus and Ito, synaptic depression at the parallel fibre to Purkinje cells synapse (pf-PC) is the main substrate responsible for learning sensorimotor contingencies under climbing fibre control. However, recent experimental evidence challenges this relatively monopolistic view of cerebellar learning. Bidirectional plasticity appears crucial for learning, in which different microzones can undergo opposite changes of synaptic strength (e.g. downbound microzones-more likely depression, upbound microzones-more likely potentiation), and multiple forms of plasticity have been identified, distributed over different cerebellar circuit synapses. Here, we have simulated classical eyeblink conditioning (CEBC) using an advanced spiking cerebellar model embedding downbound and upbound modules that are subject to multiple plasticity rules. Simulations indicate that synaptic plasticity regulates the cascade of precise spiking patterns spreading throughout the cerebellar cortex and cerebellar nuclei. CEBC was supported by plasticity at the pf-PC synapses as well as at the synapses of the molecular layer interneurons (MLIs), but only the combined switch-off of both sites of plasticity compromised learning significantly. By differentially engaging climbing fibre information and related forms of synaptic plasticity, both microzones contributed to generate a well-timed conditioned response, but it was the downbound module that played the major role in this process. The outcomes of our simulations closely align with the behavioural and electrophysiological phenotypes of mutant mice suffering from cell-specific mutations that affect processing of their PC and/or MLI synapses. Our data highlight that a synergy of bidirectional plasticity rules distributed across the cerebellum can facilitate finetuning of adaptive associative behaviours at a high spatiotemporal resolution.
Assuntos
Cerebelo , Simulação por Computador , Condicionamento Palpebral , Modelos Neurológicos , Plasticidade Neuronal , Plasticidade Neuronal/fisiologia , Animais , Cerebelo/fisiologia , Condicionamento Palpebral/fisiologia , Células de Purkinje/fisiologia , Piscadela/fisiologia , Condicionamento Clássico/fisiologia , Sinapses/fisiologia , Biologia Computacional , Camundongos , Córtex Cerebelar/fisiologiaRESUMO
Our previous studies found that the central amygdala (CeA) modulates cerebellum-dependent eyeblink conditioning (EBC) using muscimol inactivation. We also found that CeA inactivation decreases cerebellar neuronal activity during the conditional stimulus (CS) from the start of training. Based on these findings, we hypothesized that the CeA facilitates CS input to the cerebellum. The current study tested the CS facilitation hypothesis using optogenetic inhibition with archaerhodopsin (Arch) and excitation with channelrhodopsin (ChR2) of the CeA during EBC in male rats. Optogenetic manipulations were administered during the 400 ms tone CS or during a 400 ms pre-CS period. As predicted by the CS facilitation hypothesis CeA inhibition during the CS impaired EBC and CeA excitation during the CS facilitated EBC. Unexpectedly, CeA inhibition just prior to the CS also impaired EBC, while CeA excitation during the pre-CS pathway did not facilitate EBC. The results suggest that the CeA contributes to CS facilitation and vigilance during the pre-CS period. These putative functions of the CeA may be mediated through separate output pathways from the CeA to the cerebellum.
Assuntos
Núcleo Central da Amígdala , Cerebelo , Condicionamento Palpebral , Optogenética , Animais , Masculino , Cerebelo/fisiologia , Cerebelo/efeitos dos fármacos , Núcleo Central da Amígdala/fisiologia , Núcleo Central da Amígdala/efeitos dos fármacos , Condicionamento Palpebral/fisiologia , Condicionamento Palpebral/efeitos dos fármacos , Ratos , Ratos Long-Evans , Condicionamento Clássico/fisiologia , Condicionamento Clássico/efeitos dos fármacosRESUMO
Supervised learning depends on instructive signals that shape the output of neural circuits to support learned changes in behavior. Climbing fiber (CF) inputs to the cerebellar cortex represent one of the strongest candidates in the vertebrate brain for conveying neural instructive signals. However, recent studies have shown that Purkinje cell stimulation can also drive cerebellar learning and the relative importance of these two neuron types in providing instructive signals for cerebellum-dependent behaviors remains unresolved. In the present study we used cell-type-specific perturbations of various cerebellar circuit elements to systematically evaluate their contributions to delay eyeblink conditioning in mice. Our findings reveal that, although optogenetic stimulation of either CFs or Purkinje cells can drive learning under some conditions, even subtle reductions in CF signaling completely block learning to natural stimuli. We conclude that CFs and corresponding Purkinje cell complex spike events provide essential instructive signals for associative cerebellar learning.
Assuntos
Aprendizagem por Associação , Optogenética , Células de Purkinje , Animais , Células de Purkinje/fisiologia , Camundongos , Aprendizagem por Associação/fisiologia , Condicionamento Palpebral/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Cerebelo/fisiologia , Cerebelo/citologia , Fibras Nervosas/fisiologia , Camundongos Transgênicos , Córtex Cerebelar/fisiologia , FemininoRESUMO
Learning outcome is modified by the degree to which the subject responds and pays attention to specific stimuli. Our recent research suggests that presenting stimuli in contingency with a specific phase of the cardiorespiratory rhythm might expedite learning. Specifically, expiration-diastole (EXP-DIA) is beneficial for learning trace eyeblink conditioning (TEBC) compared with inspiration-systole (INS-SYS) in healthy young adults. The aim of this study was to investigate whether the same holds true in healthy elderly adults (n = 50, aged >70 yr). Participants were instructed to watch a silent nature film while TEBC trials were presented at either INS-SYS or EXP-DIA (separate groups). Learned responses were determined as eyeblinks occurring after the tone conditioned stimulus (CS), immediately preceding the air puff unconditioned stimulus (US). Participants were classified as learners if they made at least five conditioned responses (CRs). Brain responses to the stimuli were measured by electroencephalogram (EEG). Memory for the film and awareness of the CS-US contingency were evaluated with a questionnaire. As a result, participants showed robust brain responses to the CS, acquired CRs, and reported awareness of the CS-US relationship to a variable degree. There was no difference between the INS-SYS and EXP-DIA groups in any of the above. However, when only participants who learned were considered, those trained at EXP-DIA (n = 11) made more CRs than those trained at INS-SYS (n = 13). Thus, learned performance could be facilitated in those elderly who learned. However, training at a specific phase of cardiorespiratory rhythm did not increase the proportion of participants who learned.NEW & NOTEWORTHY We trained healthy elderly individuals in trace eyeblink conditioning, either at inspiration-systole or at expiration-diastole. Those who learned exhibited more conditioned responses when trained at expiration-diastole rather than inspiration-systole. However, there was no difference between the experimental groups in the proportion of individuals who learned or did not learn.
Assuntos
Condicionamento Palpebral , Humanos , Masculino , Idoso , Feminino , Condicionamento Palpebral/fisiologia , Eletroencefalografia , Idoso de 80 Anos ou mais , Frequência Cardíaca/fisiologia , Piscadela/fisiologia , Condicionamento Clássico/fisiologiaRESUMO
Limited options exist to evaluate the development of hippocampal function in young children. Research has established that trace eyeblink conditioning (EBC) relies on a functional hippocampus. Hence, we set out to investigate whether trace EBC is linked to hippocampal structure, potentially serving as a valuable indicator of hippocampal development. Our study explored potential associations between individual differences in hippocampal volume and neurite density with trace EBC performance in young children. We used onset latency of conditioned responses (CR) and percentage of conditioned responses (% CR) as measures of hippocampal-dependent associative learning. Using a sample of typically developing children aged 4 to 6 years (N = 30; 14 girls; M = 5.70 years), participants underwent T1- and diffusion-weighted MRI scans and completed a 15-min trace eyeblink conditioning task conducted outside the MRI. % CR and CR onset latency were calculated based on all trials involving tone-puff presentations and tone-alone trials. Findings revealed a connection between greater left hippocampal neurite density and delayed CR onset latency. Children with higher neurite density in the left hippocampus tended to blink closer to the onset of the unconditioned stimulus, indicating that structural variations in the hippocampus were associated with more precise timing of conditioned responses. No other relationships were observed between hippocampal volume, cerebellum volume or neurite density, hippocampal white matter connectivity and any EBC measures. Preliminary results suggest that trace EBC may serve as a straightforward yet innovative approach for studying hippocampal development in young children and populations with atypical development.
Assuntos
Condicionamento Palpebral , Criança , Feminino , Humanos , Pré-Escolar , Condicionamento Palpebral/fisiologia , Neuritos , Hipocampo/diagnóstico por imagem , Hipocampo/fisiologia , Condicionamento Clássico/fisiologia , Cerebelo/diagnóstico por imagem , PiscadelaRESUMO
Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not in climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.
Assuntos
Núcleos Cerebelares , Condicionamento Palpebral , Camundongos , Animais , Condicionamento Palpebral/fisiologia , Condicionamento Clássico/fisiologia , Cerebelo/fisiologia , Córtex Cerebelar/fisiologia , PiscadelaRESUMO
Communication between the cerebellum and forebrain structures is necessary for motor learning and has been implicated in a variety of cognitive functions. The exact nature of cerebellar-forebrain interactions supporting behavior and cognition is not known. We examined how local and network activity support learning by simultaneously recording neural activity in the cerebellum, amygdala, and anterior cingulate cortex while male and female rats were trained in trace eyeblink conditioning. Initially, the cerebellum and forebrain signal the contingency between external stimuli through increases in theta power and synchrony. Neuronal activity driving expression of the learned response was observed in the cerebellum and became evident in the anterior cingulate and amygdala as learning progressed. Aligning neural activity to the training stimuli or learned response provided a way to differentiate between learning-related activity driven by different mechanisms. Stimulus and response-related increases in theta power and coherence were observed across all three areas throughout learning. However, increases in slow gamma power and coherence were only observed when oscillations were aligned to the cerebellum-driven learned response. Percentage of learned responses, learning-related local activity, and slow gamma communication from cerebellum to forebrain all progressively increased during training. The relatively fast frequency of slow gamma provides an ideal mechanism for the cerebellum to communicate learned temporal information to the forebrain. This cerebellar response-aligned slow gamma then provides enrichment of behavior-specific temporal information to local neuronal activity in the forebrain. These dynamic network interactions likely support a wide range of behaviors and cognitive tasks that require coordination between the forebrain and cerebellum.SIGNIFICANCE STATEMENT This study presents new evidence for how dynamic learning-related changes in single neurons and neural oscillations in a cerebellar-forebrain network support associative motor learning. The current results provide an integrated mechanism for how bidirectional communication between the cerebellum and forebrain represents important external events and internal neural drive. This bidirectional communication between the cerebellum and forebrain likely supports a wide range of behaviors and cognitive tasks that require temporal precision.
Assuntos
Condicionamento Palpebral , Giro do Cíngulo , Feminino , Masculino , Ratos , Animais , Condicionamento Palpebral/fisiologia , Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Tonsila do Cerebelo/fisiologiaRESUMO
In mammals several memory systems are responsible for learning and storage of associative memory. Even apparently simple behavioral tasks, like pavlovian conditioning, have been suggested to engage, for instance, implicit and explicit memory processes. Here, we used single-whisker tactile trace eyeblink conditioning (TTEBC) to investigate learning and its neuronal bases in the mouse barrel column, the primary neocortical tactile representation of one whisker. Behavioral analysis showed that conditioned responses (CRs) are spatially highly restricted; they generalize from the principal whisker only to its direct neighbors. Within the respective neural representation, the principal column and its direct neighbors, spike activity showed a learning-related spike rate suppression starting during the late phase of conditioning stimulus (CS) presentation that was sustained throughout the stimulus-free trace period (Trace). Trial-by-trial analysis showed that learning-related activity was independent from the generation of eyelid movements within a trial, and set in around the steepest part of the learning curve. Optogenetic silencing of responses and their learning-related changes during CS and Trace epochs blocked CR acquisition but not its recall after learning. Silencing during the Trace alone, which carried major parts of the learning-related changes, had no effect. In summary, we demonstrate specific barrel column spike rate plasticity during TTEBC that can be partially decoupled from the CR, the learned eye closure, a hallmark of implicit learning. Our results, thus, point to a possible role of the barrel column in contributing to other kinds of memory as well.
Assuntos
Condicionamento Palpebral , Animais , Condicionamento Palpebral/fisiologia , Condicionamento Clássico/fisiologia , Memória/fisiologia , Córtex Cerebral , Neurônios/fisiologia , Piscadela , MamíferosRESUMO
During embryonic development, heterozygous mutant kreisler mice undergo ectopic expression of the Hoxa3 gene in the rostral hindbrain, affecting the opioid and noradrenergic systems. In this model, we have investigated behavioral and cognitive processes in their adulthood. We confirmed that pontine and locus coeruleus neuronal projections are impaired, by using startle and pain tests and by analyzing immunohistochemical localization of tyrosine hydroxylase. Our results showed that, even if kreisler mice are able to generate eyelid reflex responses, there are differences with wild-types in the first component of the response (R1), modulated by the noradrenergic system. The acquisition of conditioned motor responses is impaired in kreisler mice when using the trace but not the delay paradigm, suggesting a functional impairment in the hippocampus, subsequently confirmed by reduced quantification of alpha2a receptor mRNA expression in this area but not in the cerebellum. Moreover, we demonstrate the involvement of adrenergic projection in eyelid classical conditioning, as clonidine prevents the appearance of eyelid conditioned responses in wild-type mice. In addition, hippocampal motor learning ability was restored in kreisler mice by administration of adrenergic antagonist drugs, and a synergistic effect was observed following simultaneous administration of idazoxan and naloxone.
Assuntos
Condicionamento Clássico , Condicionamento Palpebral , Camundongos , Animais , Condicionamento Clássico/fisiologia , Neurônios/fisiologia , Condicionamento Palpebral/fisiologia , Pálpebras , Rombencéfalo/fisiologia , Proteínas de HomeodomínioRESUMO
Research has shown differences in the neural mechanisms that support trace and delay eyeblink conditioning. The present experiment furthered this investigation by examining the effect of electrolytic fornix lesions on acquisition of trace and delay eyeblink conditioning in the rat. Importantly, the conditioned stimulus (CS) for trace conditioning was a standard tone-on cue, and the CS for delay conditioning was either a tone-off or tone-on CS. The results showed that fornix lesions impaired trace-, but not delay conditioning in rats trained with the tone-on CS or tone-off CS. The findings are consistent with previous studies that found trace-, but not delay eyeblink conditioning is a hippocampal dependent form of associative learning. Our results also indicate that the neural pathways for tone-off delay conditioning and tone-on trace conditioning are different, even though the structural composition of a tone-off CS and the trace conditioning interval are the same cue (i.e., the absence of sound). These findings indicate that the absence of a sensory cue (i.e., tone-off CS) and the presence of a sensory cue (i.e., tone-on CS) have equivalent associative value and effectiveness for engaging the neural pathways that support delay eyeblink conditioning.
Assuntos
Condicionamento Palpebral , Ratos , Animais , Condicionamento Clássico , Hipocampo , Piscadela , Condicionamento OperanteRESUMO
Although recent studies have revealed an involvement of hippocampal interneurons in learning the association among time-separated events, its underlying cellular mechanisms remained not fully clarified. Here, we combined multichannel recording and optogenetics to elucidate how the hippocampal parvalbumin-expressing interneurons (PV-INs) support associative learning. To address this issue, we trained the mice (both sexes) to learn hippocampus-dependent trace eyeblink conditioning (tEBC) in which they associated a light flash conditioned stimulus (CS) with a corneal air puff unconditioned stimuli (US) separated by a 250 ms time interval. We found that the hippocampal PV-INs exhibited learning-associated sustained activity at the early stage of tEBC acquisition. Moreover, the PV-IN sustained activity was positively correlated with the occurrence of conditioned eyeblink responses at the early learning stage. Suppression of the PV-IN sustained activity impaired the acquisition of tEBC, whereas the PV-IN activity suppression had no effect on the acquisition of delay eyeblink conditioning, a hippocampus-independent learning task. Learning-associated augmentation in the excitatory pyramidal cell-to-PVIN drive may contribute to the formation of PV-IN sustained activity. Suppression of the PV-IN sustained activity disrupted hippocampal gamma but not theta band oscillation during the CS-US interval period. Gamma frequency (40 Hz) activation of the PV-INs during the CS-US interval period facilitated the acquisition of tEBC. Our current findings highlight the involvement of hippocampal PV-INs in tEBC acquisition and reveal insights into the PV-IN activity kinetics which are of key importance for the hippocampal involvement in associative learning.SIGNIFICANCE STATEMENT The cellular mechanisms underlying associative learning have not been fully clarified. Previous studies focused on the involvement of hippocampal pyramidal cells in associative learning, whereas the activity and function of hippocampal interneurons were largely neglected. We herein demonstrated the hippocampal PV-INs exhibited learning-associated sustained activity, which was required for the acquisition of tEBC. Furthermore, we showed evidence that the PV-IN sustained activity might have arisen from the learning-associated augmentation in excitatory pyramidal cell-to-PVIN drive and contributed to learning-associated augmentation in gamma band oscillation during tEBC acquisition. Our findings provide more mechanistic understanding of the cellular mechanisms underlying the hippocampal involvement in associative learning.
Assuntos
Condicionamento Palpebral , Parvalbuminas , Masculino , Feminino , Camundongos , Animais , Condicionamento Palpebral/fisiologia , Interneurônios , Hipocampo/fisiologia , PiscadelaRESUMO
Temporal contingency is a key factor in associative learning but remains weakly investigated early in life. Few data suggest simultaneous presentation is required for young to associate different stimuli, whereas adults can learn them sequentially. Here, we investigated the ability of newborn rabbits to perform sensory preconditioning and second-order conditioning using trace intervals between odor presentations. Strikingly, pups are able to associate odor stimuli with 10- and 30-sec intervals in sensory preconditioning and second-order conditioning, respectively. The effectiveness of higher-order trace conditioning in newborn rabbits reveals that very young animals can display complex learning despite their relative immaturity.
Assuntos
Condicionamento Clássico , Condicionamento Palpebral , Animais , Animais Recém-Nascidos , Condicionamento Psicológico , Aprendizagem , Odorantes , CoelhosRESUMO
Because the dentate gyrus serves as the first site for information processing in the hippocampal trisynaptic circuit, it an important structure for the formation of associative memories. Previous findings in rabbit had recorded populations of cells within dentate gyrus that may bridge the temporal gap between stimuli to support memory formation during trace eyeblink conditioning, an associative learning task. However, this previous work was unable to identify the types of cells demonstrating this type of activity. To explore these changes further, we did in vivo single-neuron recording in conjunction with physiological determination of cell types to investigate the functional role of granule cells, mossy cells, and interneurons in dentate gyrus during learning. Tetrode recordings were performed in young-adult mice during training on trace eyeblink conditioning, a hippocampal-dependent temporal associative memory task. Conditioned mice were able to successfully learn the task, with male mice learning at a faster rate than female mice. In the conditioned group, granule cells tended to show an increase in firing rate during conditioned stimulus presentation while mossy cells showed a decrease in firing rate during the trace interval and the unconditioned stimulus. Interestingly, populations of interneurons demonstrated learning-related increases and decreases in activity that began at onset of the conditioned stimulus and persisted through the trace interval. The current study also found a significant increase in theta power during stimuli presentation in conditioned animals, and this change in theta decreased over time. Ultimately, these data suggest unique involvement of granule cells, mossy cells, and interneurons in dentate gyrus in the formation of a trace associative memory. This work expands our knowledge of dentate gyrus function, helping to discern how aging and disease might disrupt this process.
Assuntos
Condicionamento Palpebral , Hipocampo , Animais , Condicionamento Clássico/fisiologia , Condicionamento Palpebral/fisiologia , Giro Denteado/fisiologia , Feminino , Hipocampo/fisiologia , Aprendizagem , Masculino , Camundongos , Neurônios/fisiologia , CoelhosRESUMO
Neuroscience techniques, including in vivo recording, have allowed for a great expansion in knowledge; however, this technology may also affect the very phenomena researchers set out to investigate. Including both female and male mice in our associative learning experiments shed light on sex differences on the impact of chronic implantation of tetrodes on learning. While previous research showed intact female mice acquired trace eyeblink conditioning faster than male and ovariectomized females, implantation of chronic microdrive arrays showed sexually dimorphic effects on learning. Microdrive implanted male mice acquired the associative learning paradigm faster than both intact and ovariectomized females. These effects were not due to the weight of the drive alone, as there were no significant sex-differences in learning of animals that received "dummy drive" implants without tetrodes lowered into the brain. Tandem mass tag mass spectrometry and western blot analysis suggest that significant alterations in the MAPK pathway, acute inflammation, and brain derived neurotrophic factor may underlie these observed sex- and surgery-dependent effects on learning.
Assuntos
Piscadela , Condicionamento Palpebral , Animais , Encéfalo , Condicionamento Clássico , Feminino , Aprendizagem , Masculino , Camundongos , Caracteres SexuaisRESUMO
Here, we investigate stimulus generalization in a cerebellar learning paradigm, called eyeblink conditioning. Mice were conditioned to close their eyes in response to a 10-kHz tone by repeatedly pairing this tone with an air puff to the eye 250 ms after tone onset. After 10 consecutive days of training, when mice showed reliable conditioned eyelid responses to the 10-kHz tone, we started to expose them to tones with other frequencies, ranging from 2 to 20 kHz. We found that mice had a strong generalization gradient, whereby the probability and amplitude of conditioned eyelid responses gradually decreases depending on the dissimilarity with the 10-kHz tone. Tones with frequencies closest to 10 kHz evoked the most and largest conditioned eyelid responses and each step away from the 10-kHz tone resulted in fewer and smaller conditioned responses (CRs). In addition, we found that tones with lower frequencies resulted in CRs that peaked earlier after tone onset compared with those to tones with higher frequencies. Together, our data show prominent generalization patterns in cerebellar learning. Since the known function of cerebellum is rapidly expanding from pure motor control to domains that include cognition, reward-learning, fear-learning, social function, and even addiction, our data imply generalization controlled by cerebellum in all these domains.
Assuntos
Condicionamento Palpebral , Animais , Piscadela , Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Condicionamento Palpebral/fisiologia , Medo , Generalização do Estímulo , CamundongosRESUMO
Rhythms of breathing and heartbeat are linked to each other as well as to the rhythms of the brain. Our recent studies suggest that presenting conditioned stimulus during expiration or during the diastolic phase of the cardiac cycle facilitates neural processing of that stimulus and improves learning in a conditioning task. To date, it has not been examined whether using information from both respiration and cardiac cycle phases simultaneously allows even more efficient modulation of learning. Here, we studied whether the timing of the conditioned stimulus to different cardiorespiratory rhythm phase combinations affects learning in a conditioning task in healthy young adults. The results were consistent with previous reports: timing the conditioned stimulus to diastole during expiration was more beneficial for learning than timing it to systole during inspiration. Cardiac cycle phase seemed to explain most of this variation in learning at the behavioral level. Brain-evoked potentials (N1) elicited by the conditioned stimulus and recorded using electroencephalogram were larger when the conditioned stimulus was presented to diastole during expiration than when it was presented to systole during inspiration. Breathing phase explained the variation in the N1 amplitude. To conclude, our findings suggest that noninvasive monitoring of bodily rhythms combined with closed-loop control of stimulation can be used to promote learning in humans. The next step will be to test if performance can also be improved in humans with compromised cognitive ability, such as in older people with memory impairments.NEW & NOTEWORTHY We report, for the first time, that the rhythms of breathing and the beating of the heart have a phase combination that is indicative of a neural state beneficial for cognition. This suggests that bodily rhythms not only modulate cognition but that this phenomenon can also be noninvasively harnessed to improve learning in humans.
Assuntos
Condicionamento Palpebral , Idoso , Piscadela , Condicionamento Clássico/fisiologia , Condicionamento Palpebral/fisiologia , Eletroencefalografia , Humanos , Respiração , Adulto JovemRESUMO
A core network of widely expressed proteins within the glutamatergic post-synapse mediates activity-dependent synaptic plasticity throughout the brain, but the specific proteomic composition of synapses differs between brain regions. Here, we address the question, how does proteomic composition affect activity-dependent protein-protein interaction networks (PINs) downstream of synaptic activity? Using quantitative multiplex co-immunoprecipitation, we compare the PIN response of in vivo or ex vivo neurons derived from different brain regions to activation by different agonists or different forms of eyeblink conditioning. We report that PINs discriminate between incoming stimuli using differential kinetics of overlapping and non-overlapping PIN parameters. Further, these "molecular logic rules" differ by brain region. We conclude that although the PIN of the glutamatergic post-synapse is expressed widely throughout the brain, its activity-dependent dynamics show remarkable stimulus-specific and brain-region-specific diversity. This diversity may help explain the challenges in developing molecule-specific drug therapies for neurological disorders.
Assuntos
Piscadela/efeitos dos fármacos , Encéfalo/metabolismo , Metoxi-Hidroxifenilglicol/análogos & derivados , N-Metilaspartato/farmacologia , Mapas de Interação de Proteínas , Proteoma/metabolismo , Sinapses/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Condicionamento Palpebral , Agonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Metoxi-Hidroxifenilglicol/farmacologia , Camundongos , Plasticidade Neuronal , Proteoma/análise , Sinapses/efeitos dos fármacosRESUMO
The developmental onset of aversive learning processes depends on complex interactions between endocrine, neural, and social influences. Emergence of avoidance conditioning in rat pups is triggered by elevated plasma corticosterone activating the amygdala. Further, the mother's ability to buffer the corticosterone response delays the onset of avoidance in Ë2-week-old pups. Eyeblink conditioning (EBC) also develops during the pre-weaning period. In previous work, little or no conditioning was observed on Day 17 for pups housed in the home cage with mother and littermates between training sessions, whereas pups isolated between training sessions did show some conditioning. This suggests that social buffering may also delay the onset of this form of aversive learning. In the present study with Day-17 pups, one session of periorbital shock, the typical EBC unconditioned stimulus for young rat pups, resulted in lower plasma corticosterone levels and neural activity in the central nucleus of the amygdale (CeA) of pups returned to the mother and homecage following the session as compared to pups isolated following the shock session. These findings demonstrate social buffering of the physiological response to aversive stimulus exposure under conditions of EBC and support the hypothesis that social buffering of early adverse experience may adjust the timing of emergence of EBC in rat pups. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Assuntos
Condicionamento Palpebral , Corticosterona , Tonsila do Cerebelo , Animais , Piscadela , Condicionamento Clássico , Feminino , Humanos , Mães , RatosRESUMO
While the hippocampus has been implicated in supporting the association among time-separated events, the underlying cellular mechanisms have not been fully clarified. Here, we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning (tEBC) task. We found that the hippocampal interneurons exhibited conditioned stimulus (CS)-evoked sustained activity, which predicted the performance of conditioned eyeblink responses (CRs) in the early acquisition of the tEBC. Consistent with this, greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC. Moreover, optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC. In contrast, suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs. Our findings highlight the role of hippocampal interneurons in the tEBC, and point to a potential cellular mechanism subserving associative learning.