Localization and characterization of an essential associative memory trace in the mammalian brain.

We argue here that we have succeeded in localizing an essential memory trace for a basic form of associative learning and memory - classical conditioning of discrete responses learned with an aversive stimulus - to the anterior interpositus nucleus of the cerebellum. We first identified the entire essential circuit, using eyelid conditioning as the model system, and used reversible inactivation, during training, of critical structures and activation of pathways to localize definitively the essential memory trace. This discovery and the associated studies have: 1) shown that the essential cerebellar circuit applies equally to all mammals studied, including humans; 2) shown that this cerebellar circuit holds for the learning of any discrete behavioral response elicited by an aversive US, not just eyelid closure; 3) identified the essential circuit and process for reinforcement for this form of learning; 4) shown that this form of learning and its essential cerebellar circuitry is phylogenetically very old; 5) solved the long-standing puzzle of where memory traces are formed in the brain when the CS is electrical stimulation of the cerebral cortex in conditioning; 6) shown that this cerebellar circuitry forms the essential neural substrate for the behavioral phenomenon of "blocking", and hence, 7) provides the first clear neural instantiation of the Rescorla-Wagner learning algorithm; 8) shown that the fundamental neural process underlying this form of learning is a strengthening of preexisting pathways, and 9) shown that the basic mechanism underlying this strengthening is the formation of new excitatory synapses.

Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit.

Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated.

An essential memory trace found.

I argue here that we have succeeded in localizing an essential memory trace for a basic form of associative learning and memory--classical conditioning of discrete responses learned with an aversive stimulus--to the anterior interpositus nucleus of the cerebellum. We first identified the entire essential circuit, using eyelid conditioning as the model system, and used reversible inactivation, during training, of critical structures and pathways to localize definitively the essential memory trace. In recognition of the 30th anniversary of Behavioral Neuroscience, I highlight 1 paper (Tracy, Thompson, Krupa, & Thompson, 1998) that was particularly significant for the progress of this research program.

Prolonging the postcomplex spike pause speeds eyeblink conditioning.

Climbing fiber input to the cerebellum is believed to serve as a teaching signal during associative, cerebellum-dependent forms of motor learning. However, it is not understood how this neural pathway coordinates changes in cerebellar circuitry during learning. Here, we use pharmacological manipulations to prolong the postcomplex spike pause, a component of the climbing fiber signal in Purkinje neurons, and show that these manipulations enhance the rate of learning in classical eyelid conditioning.

Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice.

We previously demonstrated that allopregnanolone (APα) increased proliferation of neural progenitor cells and reversed neurogenic and cognitive deficits prior to Alzheimer's disease (AD) pathology (Wang, J.M., Johnston, P.

Impaired eyeblink conditioning in 78 kDa-glucose regulated protein (GRP78)/immunoglobulin binding protein (BiP) conditional knockout mice.

Evidence grows that the cerebellum and its associated circuitry are the essential neural substrates for standard delay classical eyeblink conditioning. To further investigate the relative roles of the cerebellar cortex and nuclei in eyeblink conditioning, a novel mouse model with Purkinje cell atrophy was studied. The 78 kDa-glucose regulated protein, a chaperone molecule, was knocked out leading to postnatal Purkinje cell degeneration (Wang et al.

The cerebellum: a neural system for the study of reinforcement learning.

In its strictest application, the term "reinforcement learning" refers to a computational approach to learning in which an agent (often a machine) interacts with a mutable environment to maximize reward through trial and error. The approach borrows essentials from several fields, most notably Computer Science, Behavioral Neuroscience, and Psychology. At the most basic level, a neural system capable of mediating reinforcement learning must be able to acquire sensory information about the external environment and internal milieu (either directly or through connectivities with other brain regions), must be able to select a behavior to be executed, and must be capable of providing evaluative feedback about the success of that behavior.

c-Fos, Arc, and stargazin expression in rat eyeblink conditioning.

Neuronal plasticity induced by behavioral experience, as in memory formation, has been considered to involve transcriptional or translational changes in subsets of neurons involved in different forms of learning. Here, alteration in protein expression during cerebellar learning was investigated using rat eyeblink conditioning. After a single training session of delay conditioning, c-Fos was insignificantly increased when compared to naïve or pseudoconditioned rats.

Regulation of hippocampal synaptic plasticity by estrogen and progesterone.

Accumulating evidence indicates that the ovarian steroid hormones estrogen and progesterone regulate a wide variety of nonreproductive functions in the central nervous system by interacting with several molecular and cellular processes. A growing literature reporting results obtained in rodent models suggests that 17beta-estradiol, the most potent of the biologically relevant estrogens, facilitates some forms of learning and memory, and in particular, those involving hippocampus-dependent tasks. Hippocampal long-term potentiation and long-term depression of synaptic transmission are types of synaptic plasticity that have been extensively studied, as they are considered as cellular models of memory formation in the brain.

Involvement of cyclin-dependent kinase-like 2 in cognitive function required for contextual and spatial learning in mice.

Cyclin-dependent kinase-like 2 (Cdkl2) is a cdc2-related serine/threonine protein kinase that is postnatally expressed in various brain regions, including the cerebral cortex, entorhinal cortex, hippocampus, amygdala, and dorsal thalamus. The extremely high Cdkl2 expression in these regions suggests that it has a role in cognition and emotion. Recent genetic studies indicate that mutations of Cdkl family kinases are associated with neurodevelopmental and neuropsychiatric disorders in humans.

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease.

Our previous analyses showed that allopregnanolone (APalpha) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APalpha to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APalpha-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells.

Extra-cellular signal-regulated kinase 1/2 (ERK1/2) activated in the hippocampal CA1 neurons is critical for retrieval of auditory trace fear memory.

The brain regions involved with trace fear conditioning (TFC) and delayed fear conditioning (DFC) are well-characterized, but little is known about the cellular representation subsuming these types of classical conditioning. Previous evidence has shown that activation of the amygdala is required for both TFC and DFC, while TFC also involves the hippocampus for forming conditioned response to tone. Lesions of the hippocampus did not affect tone learning in DFC, but it impaired learning in TFC.

Differential effects and rates of normal aging in cerebellum and hippocampus.

Cognitive functions show many alternative outcomes and great individual variation during normal aging. We examined learning over the adult life span in CBA mice, along with morphological and electrophysiological substrates. Our aim was to compare cerebellum-dependent delay eyeblink classical conditioning and hippocampus-dependent contextual fear conditioning in the same animals using the same conditioned and unconditioned stimuli for eyeblink and fear conditioning.

Disruption of cerebellar cortical inhibition in the absence of learning promotes sensory-evoked eyeblink responses.

Theories of cerebellar learning propose that alterations in synaptic plasticity resulting in decreases in cerebellar cortical inhibition and increases in sensory activation of interpositus nuclei underlie the development of adaptively timed conditioned motor responses. The authors found that with concurrent pharmacological disconnection of the cerebellar cortex and intense sensory stimulation in the untrained rabbit, eyeblink responses were generated. Neither sensory stimulation nor disconnection alone generated significant eyeblink responses.

Impaired memory of eyeblink conditioning in CaMKIV KO mice.

The calcium/calmodulin-dependent protein kinase type IV (CaMKIV) is highly expressed in cerebellar cortical granule cells and deep nuclear neurons in the cerebellum. It mediates the phosphorylation and activation of the cAMP-dependent response element binding protein (CREB). In several paradigms CREB-dependent transcription is required for cellular events underlying long-term memory processes.

The role of the cerebellar interpositus nucleus in short and long term memory for trace eyeblink conditioning.

In previous studies the cerebellar interpositus (IP) nucleus, but not the hippocampus, was shown to be necessary both for initial learning and retention and for long-term retention of the standard delay eyeblink conditioned response (CR). However, in the trace eyeblink CR procedure, the hippocampus is also necessary for initial learning and retention, but not for long-term retention. Here the authors evaluate the role of the IP nucleus in both initial learning and retention, and in long-term retention of the trace eyeblink CR, using muscimol infusion to reversibly inactivate the IP nucleus.

Estrogen and hippocampal plasticity in rodent models.

Accumulating evidence indicates that ovarian hormones regulate a wide variety of non-reproductive functions in the central nervous system by interacting with several molecular and cellular processes. A growing animal literature using both adult and aged rodent models indicates that 17beta-estradiol, the most potent of the biologically relevant estrogens, facilitates some forms of learning and memory, in particular those that involve hippocampal-dependent tasks. A recently developed triple-transgenic mouse (3xTg-AD) has been widely used as an animal model of Alzheimer's disease, as this mouse exhibits an age-related and progressive neuropathological phenotype that includes both plaque and tangle pathology mainly restricted to hippocampus, amygdala and cerebral cortex.

Progesterone regulation of synaptic transmission and plasticity in rodent hippocampus.

Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the highest concentration of P4 tested (10(-6) M) decreased the baseline synaptic transmission and magnitude of LTP, but did not affect LTD.

Habituation revisited: an updated and revised description of the behavioral characteristics of habituation.

The most commonly cited descriptions of the behavioral characteristics of habituation come from two papers published almost 40 years ago [Groves, P. M., & Thompson, R.

17beta-estradiol modifies stress-induced and age-related changes in hippocampal synaptic plasticity.

The female steroid hormone 17beta-estradiol enhances synaptic transmission and the magnitude of longterm potentiation (LTP) in adult rodent hippocampal slices. Long-term depression (LTD), another form of synaptic plasticity, occurs more prominently in hippocampal slices from aged rodents. A decrease in LTP has been recorded in hippocampal slices from adult rodents behaviorally stressed just before tissue preparation and electrophysiological recording.

Progesterone receptors: form and function in brain.

Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system to regulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. Progesterone-regulated neural responses are mediated by an array of progesterone receptors (PR) that include the classic nuclear PRA and PRB receptors and splice variants of each, the seven transmembrane domain 7TMPRbeta and the membrane-associated 25-Dx PR (PGRMC1). These PRs induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors.

Extinction of a classically conditioned response: red nucleus and interpositus.

It is well established that the cerebellum and its associated circuitry are essential for classical conditioning of the eyeblink response and other discrete motor responses (e.g., limb flexion, head turn, etc.

Eye-blink conditioning is associated with changes in synaptic ultrastructure in the rabbit interpositus nuclei.

Eye-blink conditioning involves the pairing of a conditioned stimulus (usually a tone) to an unconditioned stimulus (air puff), and it is well established that an intact cerebellum and interpositus nucleus, in particular, are required for this form of classical conditioning. Changes in synaptic number or structure have long been proposed as a mechanism that may underlie learning and memory, but localizing these changes has been difficult. Thus, the current experiment took advantage of the large amount of research conducted on the neural circuitry that supports eye-blink conditioning by examining synaptic changes in the rabbit interpositus nucleus.