Susan Sara

Georges Chapouthier

The Pharmacology of Memory

The present review focuses on the hypothesisthat norepinephrine (NE) and dopamine (DA)act as learning signals. Both NE and DA arebroadly distributed in areas concerned with therepresentation of the world and with theconjunction of sensory inputs and motor outputs.Both are released at times of novelty anduncertainty, providing plausible signal eventsfor updating representations and associations.These catecholamines activate intracellularmachinery postulated to serve as a memory-formationcascade. Yet, despite the plausibilityof an NE and DA role in vertebrate learningand memory, most evidence that they provide alearning signal is circumstantial. The majorweakness of the data available is the lack of aspecific description of how the neural circuitmodulated by NE or DA participates in thelearning being analyzed. Identifying a conditionedstimuli (CS) representation would facilitate theidentification of a learning signal role for NE orDA. Describing how the CS representationcomes to relate to learned behavior, eitherthrough sensory-sensory associations, in whichthe CS acquires the motivational significance ofreward or punishment, thus driving appropriatebehavior, or through direct sensory-motorassociations is necessary to identify how NE and DA participate in memory creation. Asdescribed here, evidence consistent with adirect learning signal role for NE and DA isseen in the changing of sensory circuits in odorpreference learning (NE), defensive conditioning(NE), and auditory cortex remodeling in adultrats (DA). Evidence that NE and DA contributeto normal learning through unspecifiedmechanisms is extensive, but the details of thatsupport role are lacking.

Carolyn W. Harley

Norepinephrine and Dopamine as Learning Signals

Functional and morphological studies in
children affected by Attention Deficit Hyperactivity
Disorder (ADHD) suggest a prefrontal
cortex (PFc) dysfunction. This cortical region is
regulated by subcortical systems including noradrenergic
(NEergic), dopaminergic (DAergic),
cholinergic, serotonergic, and histaminergic pathways.
A wealth of data in humans and in animal
models demonstrates altered dopamine (DA)
regulation. Drugs that modulate norepinephrine
(NE) transmission are also effective in ADHD
patients, thus leading to the hypothesis of a
NEergic disorder. This review covers the
regulation of PFc functions by NE and the
interaction between the NE and DA systems, as
suggested by pharmacological, electrophysiological,
morphological, and gene knock out (KO)
studies. A negative feedback between NE and DA
neurons emerges from KO studies because KO
mice showing increased (NE transporter (NET)
KO) or decreased (DBH and VMAT2 KO) NE
levels are respectively associated with lower and
higher DA levels. Locomotor activity can be
generally predicted by the DA level, whereas
sensitivity to amphetamines is by NE/DA balance.
Some animal models of ADHD, such as
spontaneously hypertensive rats (SHR), show
alterations in the PFc and in the DA system.
Evidence about a correlation between the NE
system and hyper-locomotion activity in such
animals has not yet been clarified. Therefore, this
review also includes recent evidence on the
behavioral effects of two NET blockers,
reboxetine and atomoxetine, in two animal models
of ADHD: SHR and Naples High Excitability rats.
As these drugs modulate the DA level in the PFc,
certain effects are likely to be due to a rebalanced
DA system. We discuss the significance of the
results for theories of ADHD and make
suggestions for future experimentation.

D. Viggiano

L. A. Ruocco

S. Arcieri

A. G. Sadile

Involvement of Norepinephrine in the Control of Activity and Attentive Processes in Animal Models of Attention Deficit Hyperactivity Disorder

The history of the neurochemistry of mnesicprocesses can be divided into two main periods:the first (1946-1978) was inspired by the resultsof molecular genetics, providing evidence forstorage of hereditary information in the DNAof genes. Therefore, the chemical bases formemory were investigated in the macromoleculesof the brain. Such attempts wererelatively unsuccessful, which led to a secondperiod (starting in 1978) with the researchemphasizing, in a less ambitious way, the role ofthe molecular correlates of mnesic processes, inparticular in the main transmitter systems ofthe brain.

Georges  Chapouthier

From the Search for a Molecular Code of Memory to the Role of Neurotransmitters: A Historical Perspective

Electroretinogram (ERG), widely used to
study the pharmacological effects of drugs in
animal models (e.g., diabetic retinopathy), is
usually recorded in anesthetized rats. We report
here a novel simple method to obtain chronic
implantation of electrodes for simultaneous
recording at the retinal and cortical levels in
freely moving, unanesthetized animals. We
recorded cortical (VEPs) and retinal (ERGs)
responses evoked by light (flash) stimuli in
awake rats and compared the results in the
same rats anesthetized with urethane (0.6
mg/kg) before and after the monocular administration
of scopolamine methyl bromide (1
solution). We also compared the retinal
responses with those derived from a classic acute
corneal electrode. Anesthesia induced consistent
changes of several VEP and ERG parameters
like an increase of both latency and amplitude.
In particular, the analysis of the variation of
latency, amplitude, and spectral content of
rapid oscillatory potentials could be important
for a functional evaluation of the visual system
in unanesthetized versus anesthetized animals.

Irene Guarino

Stefano Loizzo

Luisa Lopez

Antonello Fadda

Alberto Loizzo

A Chronic Implant to Record Electroretinogram, Visual Evoked Potentials and Oscillatory Potentials in Awake, Freely Moving Rats for Pharmacological Studies

We have advanced considerably in the past2 to 3 years in understanding the molecularmechanisms of consolidation, retrieval, andextinction of memories, particularly of fearmemory. This advance was mainly due topharmacological studies in many laboratoriesusing localized brain injections of molecularlyspecific substances. One area in which significantadvances have been made is in understandingthat many different brain structures areinvolved in different memories, and that oftenseveral brain regions are involved in processingthe same memory. These regions can cooperateor compete with each other, depending oncircumstances that are beginning to beidentified quite clearly. Another aspect inwhich major advances were made was retrievaland post-retrieval events, especially extinction,pointing to new therapeutic approaches to fearmotivatedmental disorders.

Iv&#225;n  Izquierdo

Mart&#237;n  Cammarota

Jorge H. Medina

Lia R. M. Bevilaqua

Pharmacological Findings on the Biochemical Bases of Memory Processes: A General View

In this minireview, we discuss different strategies to dissect genetically the keystones of learning and memory. First, we broadly sketch the neurogenetic analysis of complex traits in mice. We then discuss two general strategies to find genes affecting learning and memory: candidate gene studies and whole genome searches. Next, we briefly review more recently developed techniques, such as microarrays and RNA interference. In addition, we focus on gene-environment interactions and endophenotypes. All sections are illustrated with examples from the learning and memory field, including a table summarizing the latest information about genes that have been shown to have effects on learning and memory.

Yann S. Mineur

Wim E. Crusio

Frans  Sluyter

Genetic Dissection of Learning and Memory in Mice

Mendelian genetic tools have extensivelybeen used to improve the description of thepharmacological mechanisms involved inlearning and memory. The first part of thisshort review describes experiments involvingthe bidirectional selection of rats or mice forextreme behavioral characteristics or forsensitivity to pharmacological treatments.The second part focuses specifically on inbreeding.In conclusion, the advantages andthe limits of a Mendelian pharmacogeneticapproach of learning and memory arediscussed.

Martine  Ammassari-Teule

Claudio  Castellano

Strains of Rodents and the Pharmacology of Learning and Memory

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Neural Plasticity is an interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology.

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Chief Editor, Professor Baudry, is currently University Professor at Western University of Health Sciences in Pomona, CA. His research focuses on understanding the molecular/cellular mechanisms of learning and memory and neurodegeneration.

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