Activity Of Hippocampal Pyramidal Neurons Research Articles

Molecular targets for optogenetic stimulation of astrocytes for recovering cognitive functions in neurological complications

Recently, mounting evidence suggests that cognitive impairment may accompany traditional neurological diseases, such as neurodegenerative disorders, as well as result from previous infections (COVID-19, influenza). One approach to mitigating the neurological pathological state involves regulating abnormal neural activity. Nevertheless, addressing this issue directly may not always be feasible due to neuronal overexcitation or inadequate stimulation, leading to unfavorable outcomes. Meanwhile, astrocytes adapt their activation levels exclusively to the group of neurons requiring activation, boosting cognitive functions as an example [1]. Optogenetics was employed in this study to selectively stimulate metabotropic astrocyte receptors in acute hippocampal slices of mice with an Alzheimer’s model. The aim was to examine the effect on electrophysiological function of neurons, strength of synaptic contacts ex vivo, and cognitive performance in vivo. Several fundamentally different approaches exist for optogenetic stimulation of cells, including the use of molecular targets such as ionotropic receptors (e.g., ChR2) or metabotropic receptors (e.g., OptoGq). Our studies have shown enhanced activity of hippocampal pyramidal neurons and potentiated field excitatory potentials (fEPSP) following optogenetic activation of astrocytes expressing the metabotropic construct OptoGq. Conversely, the use of ChR2 resulted in an opposite effect [2]. For this reason, all subsequent investigations used a metabotropic construct. Astrocytes are known to respond to external stimuli via intracellular calcium [Ca2+] waves. The propagation of this wave results in the release of D-serine, cytokines, and lactate, subsequently modulating the activity of neurons. The role of astrocytes in regulating the function of NMDA receptors by releasing or removing glutamate from the extracellular environment is critical in modulating neural network excitation. Given the association of astrocytes with the pathogenesis and pathological mechanisms involved in neurodegenerative disorders, controlling their activity becomes a pressing and indispensable aspect of therapy. In the present investigation, optogenetic stimulation of hippocampal astrocytes transduced by AAV5_GfaABC1D_opto-a1AR-EYFP virus (which encodes a Gq-coupled metabotropic receptor) resulted in enhanced electrophysiological activity of hippocampal pyramidal neurons. This was evidenced by increased sEPSC of pyramidal neurons and the potentiation of field excitatory postsynaptic potentials (fEPSP) in the hippocampal region, following light activation of astrocytes [2]. A significant activation of early gene expression (cRel, Arc, Fos, JunB, and Egr1) was detected in hippocampal slices [3]. Additionally, optogenetic activation of the metabotropic receptor during behavioral tests in vivo restored cognitive functions in mice with an Alzheimer’s disease model. The activation of the Gq-coupled metabotropic receptor was found to be a molecular target that promotes positive changes in neuronal functioning at ex vivo and in vivo levels in both wild type mice and a mouse model of Alzheimer’s disease. Expression of OPTO-α1AR in astrocytes could potentially have a beneficial impact on other neuropathological conditions. In the future, alternative less-invasive methods, such as chemogenetics, could be employed to specifically activate astrocytes in distinct brain regions.

The Combined Effect of Donepezil and Lovastatin on the Electrical Activity of Hippocampal Pyramidal Neurons in a rat model of Alzheimer’s disease

Background: Donepezil, a noncompetitive acetylcholinesterase inhibitor, is prescribed to treat mild to moderate Alzheimer's disease but it only has moderate performance. Therefore, combination therapies are more effective. There is much evidence suggesting that statins have neuroprotective effects on neurological disorders including Alzheimer's disease. The present study aimed to investigate the combined effects of Donepezil and Lovastatin on the activity of the pyramidal neurons of the CA1 hippocampus.
 Methods: In the present experiment study, adult male rats were divided into 3 groups: Nucleus Basalis Magnocellularis (NBM) lesion (which received electrically- induced lesion (0.5 mA, 3s) in NBM) group, NBM lesion + injection Donepezil 5mg/kg-Lovastatin 10mg/kg, NBM lesion+ injection Donepezil 15mg/kg-Lovastatin 30mg/kg. Spontaneous activity of pyramidal neurons in CA1 region to injection of Donepezil-Lovastatin was investigated in a rat model of Alzheimer's disease.
 Results: The results of this study showed that electrical lesion of NBM leads to a decrease in the activity frequency of pyramidal neurons in the CA1 region. Administration of Donepezil 5mg/kg-Lovastatin 10mg/kg increased the frequency of pyramidal neurons in rat model of Alzheimer's disease.
 Conclusion: The results of this study suggest that co-administration of Donepezil-Lovastatin (low doses) increases the activity of the CA1 pyramidal neurons in a rat model of Alzheimer’s disease.

Pentylenetetrazol-induced seizures are followed by a reduction in the multiunitary activity of hippocampal CA1 pyramidal neurons in adult rats

Pentylenetetrazol (PTZ) blocks the inhibitory action of GABA, triggering a Glu-mediated hyperexcitation of the dendritic spines in hippocampal CA1 pyramidal neurons that leads to the generation of epileptiform seizures. The aim of this work was to determine the effect of PTZ on the electrical activity of the hippocampal pyramidal neurons in male rats. Bipolar electrodes were implanted stereotaxically in the right and left hippocampal CA1 fields of adults, and PTZ (65 mg/kg) was administered i.p. Simultaneous recordings of the field activity and the firing rate (multiunitary activity, MUA) were analyzed at 10, 20, and 30 min post-administration of PTZ. Only rats that presented tonic-clonic seizures during the first 1–5 min after PTZ treatment were included in the study. The recordings of the field activity were analyzed in 4 frequency bands. In both the right and left hippocampal CA1 fields, the relative power corresponding to the slow waves (4–7 Hz) increased, while in the bands 13–30 Hz and 31–50 Hz, it decreased at 10, 20, and 30 min post-PTZ. MUA recordings were analyzed at four levels. The highest levels corresponded to larger amplitudes of the action potentials in the pyramidal neurons. The firing rates of the PTZ-treated rats did not differ from baseline but presented a significant decrement at 10, 20, and 30 min post-PTZ. The decreased firing rate of the hippocampal CA1 pyramidal neurons after PTZ treatment could be associated with plastic changes of dendritic spines along with some microenvironmental adaptations at synaptic level, after neuronal PTZ-mediated hyperexcitation.

Long-duration hippocampal sharp wave ripples improve memory.

Hippocampal sharp wave ripples (SPW-Rs) have been hypothesized as a mechanism for memory consolidation and action planning. The duration of ripples shows a skewed distribution with a minority of long-duration events. We discovered that long-duration ripples are increased in situations demanding memory in rats. Prolongation of spontaneously occurring ripples by optogenetic stimulation, but not randomly induced ripples, increased memory during maze learning. The neuronal content of randomly induced ripples was similar to short-duration spontaneous ripples and contained little spatial information. The spike content of the optogenetically prolonged ripples was biased by the ongoing, naturally initiated neuronal sequences. Prolonged ripples recruited new neurons that represented either arm of the maze. Long-duration hippocampal SPW-Rs replaying large parts of planned routes are critical for memory.

Longer ripples make better memories

Neuroscience Sharp wave ripples in the hippocampus are thought to play a role in memory formation and action planning. Fernandez-Ruiz et al. used multisite electrophysiological recordings combined with optogenetic activation of hippocampal pyramidal neurons in rats performing learning tasks. Learning and correct recall in spatial memory tasks were associated with extended sharp wave ripples. Artificially prolonging these ripples improved working memory performance, whereas aborting the late part of ripples decreased performance. Science , this issue p. [1082][1] [1]: /lookup/doi/10.1126/science.aax0758

Organization of Activity of Hippocampal Pyramidal Neurons under Coactivation of Dendritic Glutamate- and GABA-Sensitive Receptors: a Simulation Study

Using the model of a hippocampal pyramidal neuron with reconstructed dendritic arborization having active electrical properties of the membrane, we investigated the effects of tonic activation of dendritic receptor channels sensitive to glutamate and GABA on the patterns of impulse activity in the axon and on the corresponding electrical processes in the dendrites. Activation of these types of receptors was represented by introducing the uniformly distributed membrane conductivities G se and G si associated with the current reversal potentials of 0 and -60 mV, respectively. It was found that the dendritic membrane with voltage-gated ion channels typical of this-type neurons became, under the influence of suprathreshold activation of glutamate receptors, a source of self-oscillations of the membrane potential or persistent depolarization of the membrane with characteristic differences of the electrical processes in metrically asymmetrical parts of the dendritic arborization. At the neuronal output, regular periodic or stochastic sequences of action potentials (APs) were generated; their average repetition frequency f depended logarithmically on the G se. Coactivation of GABA receptors (G si > 0) led to an increase in the threshold and a decrease in the frequency of auto-oscillations in the dendrites (in this case, the autooscillations were renewed in the branches where persistent depolarization developed previously), as well as to a decrease in the mean frequency of AP firing, whereas the logarithmic dependence of f on the G se remained. An earlier undescribed effect was revealed; the transformation of firing patterns (irregular, stochastic, and regular, periodic) at certain ratios of the conductivities G se and G si occurred. It is assumed that the above-described features of the firing pattern formation in hippocampal pyramidal neurons are due to dynamical spatial coupling of the local auto-oscillatory processes. This coupling depends on the geometry and membrane conductivities of the dendrites, is modulated by coactivation of receptors of different types, and is determined by the parametric sensitivity of the dendritic transfer functions.

Antibiotic supplements affect electrophysiological properties and excitability of rat hippocampal pyramidal neurons in primary culture.

Antibiotic supplements are regularly used in neuronal culture media to control contamination; however, they can interfere with the neuronal excitability and affect electrophysiological properties. Therefore, in this study, the effect of penicillin/streptomycin supplements on the spontaneous electrophysiological activity of hippocampal pyramidal neurons was examined. Electrophysiological whole-cell patch-clamp recordings from rat hippocampal pyramidal cells in primary culture were performed to investigate the effects of antibiotic supplements on the intrinsic excitability of cultured cells. The present findings indicated that presence of antibiotic supplements (penicillin/streptomycin) in the culture medium altered the intrinsic electrical activity of hippocampal pyramidal neurons in primary culture. These alterations included: 1) depolarized resting membrane potential; 2) a significant enhancement in the after-hyperpolarization amplitude; 3) a significant increase in the area under the action potential and in the decay and rise time of the action potential; 4) a significant broadening of action potential and 5) a significant reduction in the firing frequency. These findings suggest that addition of antibiotic supplements to culture media influences the neuronal excitability and alters the electrophysiological properties of cultured neurons, possibly through changing the ionic conductance underlying neuronal excitability.

In vivo dual intra- and extracellular recordings suggest bidirectional coupling between CA1 pyramidal neurons

Spikelets, small spikelike membrane potential deflections, are prominent in the activity of hippocampal pyramidal neurons in vivo. The origin of spikelets is still a source of much controversy. Somatically recorded spikelets have been postulated to originate from dendritic spikes, ectopic spikes, or spikes in an electrically coupled neuron. To differentiate between the different proposed mechanisms we used a dual recording approach in which we simultaneously recorded the intracellular activity of one CA1 pyramidal neuron and the extracellular activity in its vicinity, thus monitoring extracellularly the activity of both the intracellularly recorded cell as well as other units in its surroundings. Spikelets were observed in a quarter of our recordings (n = 36). In eight of these nine recordings a second extracellular unit fired in correlation with spikelet occurrences. This observation is consistent with the idea that the spikelets reflect action potentials of electrically coupled nearby neurons. The extracellular spikes of these secondary units preceded the onset of spikelets. While the intracellular spikelet amplitude was voltage dependent, the simultaneously recorded extracellular unit remained unchanged. Spikelets often triggered action potentials in neurons, resulting in a characteristic 1- to 2-ms delay between spikelet onset and firing. Here we show that this relationship is bidirectional, with spikes being triggered by and also triggering spikelets. Secondary units, coupled to pyramidal neurons, showed discharge patterns similar to the recorded pyramidal neuron. These findings suggest that spikelets reflect spikes in an electrically coupled neighboring neuron, most likely of pyramidal cell type. Such coupling might contribute to the synchronization of pyramidal neurons with millisecond precision.

Neuronal Models for Sleep-Wake Regulation and Synaptic Reorganization in the Sleeping Hippocampus

In this article, we discuss mathematical models that address the control of sleep-wake behavior in the infant and adult rodent and a model that addresses changes in single-cell firing patterns in the hippocampus across wake and rapid eye movement (REM) sleep states. Each of the models describes the dynamics of experimentally identified neuronal components--either the firing activity of wake-and sleep-promoting neuronal populations or the spiking activity of hippocampal pyramidal neurons. Our discussion of each model illustrates how a mathematical model that describes the temporal dynamics of the modeled neuronal components can reveal specifics about proposed neuronal mechanisms that underlie sleep-wake regulation or sleep-specific firing patterns. For example, the dynamics of the models developed for sleep-wake regulation in the infant rodent lend insight into the involved brain-stem neuronal populations and the evolution of the network during maturation. The results of the model for sleep-wake regulation in the adult rodent suggest distinct properties of the involved neuronal populations and their interactions that account for long-lasting and brief waking bouts. The dynamics of the model for sleep-specific hippocampal neural activity proposes neural mechanisms to account for observed activity changes that can invoke synaptic reorganization associated with learning and memory consolidation.

Population model of hippocampal pyramidal neurons, linking a refractory density approach to conductance-based neurons

We propose a macroscopic approach toward realistic simulations of the population activity of hippocampal pyramidal neurons, based on the known refractory density equation with a different hazard function and on a different single-neuron threshold model. The threshold model is a conductance-based model taking into account adaptation-providing currents, which is reduced by omitting the fast sodium current and instead using an explicit threshold criterion for action potential events. Compared to the full pyramidal neuron model, the threshold model well approximates spike-time moments, postspike refractory states, and postsynaptic current integration. The dynamics of a neural population continuum are described by a set of one-dimensional partial differential equations in terms of the distributions of the refractory density (where the refractory state is defined by the time elapsed since the last action potential), the membrane potential, and the gating variables of the voltage-dependent channels, across the entire population. As the source term in the density equation, the probability density of firing, or hazard function, is derived from the Fokker-Planck (FP) equation, assuming that a single neuron is governed by a deterministic average-across-population input and a noise term. A self-similar solution of the FP equation in the subthreshold regime is obtained. Responses of the ensemble to stimulation by a current step and oscillating current are simulated and compared with individual neuron simulations. An example of interictal-like activity of a population of all-to-all connected excitatory neurons is presented.

Activation of Hippocampal Pyramidal Neurons N-Methyl-D-Aspartate Receptors and M-cholinoreceptors During the Application of Amanita (Pers.: Fr.) Hook. Species Extracts

Activation of Hippocampal Pyramidal Neurons N-Methyl-D-Aspartate Receptors and M-cholinoreceptors During the Application of Amanita (Pers.: Fr.) Hook. Species Extracts

Chapter 22 An adenosine A3 receptor-selective agonist does not modulate calcium-activated potassium currents in hippocampal CA1 pyramidal neurons

This chapter presents the effects of a selective A 3 agonist, 2 - chloro - N6 - (3 - iodobenzyl)-adenosine - 5' - N - methyluronamide (Cl-IB-MECA), are characterized on hippocampal CA 1 pyramidal neurons. The chapter examines the possibility that activation of A 3 receptors could lead to activation of protein kinase A (PKA), protein kinase C (PKC), or calcium/calmodulin dependent protein kinase II (CaM-K), which might then induce significant changes in the activity of hippocampal pyramidal neurons. CA1 pyramidal neurons were recorded in the whole cell mode using patch electrodes, and the effects of adenosine agonists were determined on the holding current, and on the amplitude of the slow outward calcium-activated K + currents activated following a depolarizing step in the command voltage Z (I AHP ). The result discussed in the chapter suggest that either A 3 receptors are not present on the cell bodies of hippocampal CA1 pyramidal neurons; that they are present but not linked to PKA, PKC, or CaM-K activation; or that they only activate these kinases in cell compartments that are not accessible to the ion channels that underlie the AHP response.

Activity of hippocampal pyramidal neurons during trace eyeblink conditioning.

The responsiveness of hippocampal pyramidal neurons was examined in young adult rabbits which were trained in a hippocampally dependent long interval trace eyeblink conditioning task. The majority of recorded cells were putative pyramidal neurons from area CA1. Our analysis indicates that 57% of 93 neurons had a statistically significant change in firing rate during some portion of the trial. The response patterns were quite heterogeneous, and inhibition was frequently observed. Inhibition was especially prominent in a post-trial period. Only a small percentage of the putative pyramidal cells exhibited robust changes in activity with prominent temporal modeling of the conditioned eyeblink response as previously described for rabbits trained with delay conditioning procedures (Berger et al. [1983] J Neurophysiol 50:1197-1219). These results were also similar for the CA3 pyramidal neurons that were recorded (N = 19). Few CA1 neurons had significant responses during unpaired presentations of tone and airpuff, and neural activity that was present was concentrated in the period commencing from airpuff onset. Preliminary data were also recorded from putative pyramidal neurons during hippocampally independent delay eyeblink conditioning, where a longer tone overlapped and coterminated with the airpuff. In this task five of 13 neurons (CA1 and CA3) were active during the trial period, another four were responsive only during the post-trial period, and other simultaneously recorded neurons were unresponsive. These data suggest a relatively more varied pattern of pyramidal neuron engagement during hippocampally dependent trace eyeblink conditioning than was apparent in previous multiple- and single-neuron analyses of activity during eyeblink conditioning.

614 The distribution of neurons containing nicotinamide adenine dinucleotide phosphate diaphorase in the cerebral cortex of schizophrenic patients

Benzodiazepines (BZD) have been reported to suppres cholecystokinin-8S (CCK-8S)-induced activation. PK 8165, a ligand of BZD receptors, is an anxiolytic devoid of sedative and anticonvulsant effects. PK 8165, applied microiontophoretically or administered i.v. at low doses, suppresed CCK-8S-induced activation of hippocampal pyramidal neurons, whereas, at high doses it antagonized the effect of microiontophoretic applications of flurazepam. These results indicate that PK 8165 acts as a mixed agonist-antagonist at BZD receptors and suggest that the suppression of CCK-8S-induced activation by BZD might be related to their anxiolytic property rather than to their sedative or anticonvulsant activity.

613 Role of basic fibroblast growth factor in the regulation of rat basilar artery tone in vivo

Benzodiazepines (BZD) have been reported to suppres cholecystokinin-8S (CCK-8S)-induced activation. PK 8165, a ligand of BZD receptors, is an anxiolytic devoid of sedative and anticonvulsant effects. PK 8165, applied microiontophoretically or administered i.v. at low doses, suppresed CCK-8S-induced activation of hippocampal pyramidal neurons, whereas, at high doses it antagonized the effect of microiontophoretic applications of flurazepam. These results indicate that PK 8165 acts as a mixed agonist-antagonist at BZD receptors and suggest that the suppression of CCK-8S-induced activation by BZD might be related to their anxiolytic property rather than to their sedative or anticonvulsant activity.

Nimodipine enhances spontaneous activity of hippocampal pyramidal neurons in aging rabbits at a dose that facilitates associative learning

The functional activity of hippocampal neurons is strongly correlated with behavioral performance in a vertebrate model learning system, rabbit eyeblink conditioning. Using this system, we have previously shown that (a) complete removal of the hippocampus blocks acquisition of the conditioned response; (b) a calcium-dependent postsynaptic afterhyperpolarization is reduced in pyramidal cells recorded intracellularly in hippocampal slices taken from conditioned rabbits; and (c) nimodipine, a 1,4-dihydropyridine calcium-channel antagonist, facilitates acquisition of the conditioned response in aging rabbits. Although calcium-channel antagonists directly block neuronal calcium currents in vitro, they also alter cerebral blood flow in vivo. Thus, the effects of nimodipine on hippocampal neuronal activity in awake animals were examined, with controls for cerebrovascular changes. A total of 457 pyramidal cells and 160 theta cells were studied. During infusion of nimodipine, pyramidal cell firing activity was enhanced and theta interneuron activity was suppressed at all doses tested in aging animals. This effect was rapidly reversed when infusion of the drug ceased. The greatest enhancement of neuronal firing was seen at the most behaviorally effective dose of nimodipine. The enhancement of pyramidal cell firing was age-dependent with greater increases in firing activity seen in aging than in young animals, but with a similar dose-dependent pattern of effects in the two age groups. Two other calcium-channel antagonists, nifedipine and flunarizine, did not significantly alter spontaneous firing rates of hippocampal neurons. A calcium-channel agonist, BAY-K-8644, produced less easily interpretable results. BAY-K-8644 enhanced interneuron activity at one dose, but enhanced pyramidal cell activity at a dose one log unit higher. The calcium-channel agonist's enhancement of pyramidal cell actvity at highest dose was sustained up to 1 h after drug infusion. Nimodipine's enhancement of the activity of hippocampal pyamidal cells is consistent with the hypothesis that these neurons, which play a necessary role in some forms of learning, may mediate the calcium-channel antagonist's behavioral effects.

Inhibition of hippocampal CA 1 neurons by 5-hydroxytryptamine, derived from the dorsal raphe nucleus and the 5-hydroxytryptamine 1A agonist SM-3997

Electrophysiological studies, using chloral hydrate-anesthetized rats, were undertaken to determine whether hippocampal pyramidal neurons, receiving input from the medial septal nucleus, were affected by 5-hydroxytryptamine (5-HT) derived from the dorsal raphe nucleus. The pyramidal neurons in the CA 1 region of the hippocampus were classified into short- and long-latency neurons, based on their response to stimulation of the medial septal nucleus. Microiontophoretically applied atropine inhibited the generation of spikes upon stimulation of the medial septal nucleus in short-latency neurons, but had no effect on long-latency neurons. In the short-latency neurons, the stimulation-induced spikes of the medial septal nucleus were inhibited by conditioning stimuli applied to the dorsal raphe nucleus and iontophoretic application of 5-HT and the 5-HT 1A agonists, SM-3997 (3aα,4β,7β,7aα-hexahydro-2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)-butyl)-4,7-methano-1H-isoindole-1,3(2H)-dione dihydrogen citrate) and 8-OH-DPAT (8-hydroxy-2-(di- n-propylamino)tetralin). The conditioning effect of the dorsal raphe nucleus was antagonized by methysergide. However, in the long-latency neurons, the spikes elicited by stimulation of the medial septal nucleus were not affected by the conditioning stimulation of the dorsal raphe nucleus, or iontophoretically applied 5-HT. These results indicate that 5-HT, originating in the dorsal raphe nucleus inhibited hippocampal pyramidal neurons receiving cholinergic input from the medial septal nucleus, but not those receiving non-cholinergic input from the medial septal nucleus. The drug SM-3997 inhibited the activity of hippocampal pyramidal neurons, that receive excitatory cholinergic input from the medial septal nucleus by acting on 5-HT 1A receptors.

Long-term antidepressant treatment reduces neuronal responsiveness to flurazepam: an electrophysiological study in the rat.

Long-term administration of various types of antidepressant drugs has been recently reported to reduce the density of benzodiazepine receptors in the rat CNS. In the present study, using the microiontophoretic technique, the effect of flurazepam application on cholecystokinin-induced activation of hippocampal pyramidal neurons was assessed in rats treated with the antidepressants desipramine, trimipramine and citalopram, and the antipsychotic chlorpromazine, for 3 weeks. All 3 antidepressant drugs, but not chlorpromazine, reduced the efficacy of flurazepam. A two-week treatment with desipramine produced a similar effect, whereas a one-week treatment with this drug failed to alter the effect of flurazepam. These results constitute further evidence that long-term antidepressant treatment down-regulates benzodiazepine receptors.

Effects of PK 8165, a partial benzodiazepine receptor agonist, on cholecystokinin-induced activation of hippocampal pyramidal neurons: A microiontophoretic study in the rat

Benzodiazepines (BZD) have been reported to suppres cholecystokinin-8S (CCK-8S)-induced activation. PK 8165, a ligand of BZD receptors, is an anxiolytic devoid of sedative and anticonvulsant effects. PK 8165, applied microiontophoretically or administered i.v. at low doses, suppresed CCK-8S-induced activation of hippocampal pyramidal neurons, whereas, at high doses it antagonized the effect of microiontophoretic applications of flurazepam. These results indicate that PK 8165 acts as a mixed agonist-antagonist at BZD receptors and suggest that the suppression of CCK-8S-induced activation by BZD might be related to their anxiolytic property rather than to their sedative or anticonvulsant activity.

Hippocampectomy selectively disrupts discrimination reversal conditioning of the rabbit nictitating membrane response

The effects of hippocampal lesions were tested on two-tone discrimination reversal conditioning of the rabbit nictitating membrane response. Results showed that hippocampectomized animals learned the initial two-tone discrimination at rates equivalent to operated control animals and animals with neocortical lesions. During reversal conditioning, however, animals with hippocampal lesions were severely impaired relative to both other groups. Neocortical lesions were without effect on reversal learning. An additional study revealed that the hippocampectomized animals' failure at reversal could not be attributed to a lesion-induced increased resistance to extinction. Results are discussed with respect to several theories of hippocampal function, and with respect to changes in the activity of hippocampal pyramidal neurons which occur during classical conditioning of the nictitating membrane response.