Intracerebral muscimol injection is widely used to inactivate discrete brain structures during behavioral tasks. However, little effort has been made to quantify the extent of muscimol diffusion. The authors report here electrophysiological and autoradiographic results obtained after muscimol injection (1 microg/microl) either into the nucleus basalis magnocellularis (0.1-0.4 microl) or into the thalamic reticular nucleus (RE, 0.05-0.1 microl). In 52 rats, multiunit recordings were collected either in the RE or in the auditory thalamus during the 2 h following muscimol injection. Decreases in neuronal activity were observed up to 3 mm from the injection site; their time of occurrence was a function of the distance between the injection and recording sites. Because these decreases cannot be explained by physiological effects, they likely reflected muscimol diffusion up to the recording sites. Autoradiographic studies involved 25 rats and different experimental conditions. Optical density (OD) measures indicated that after a survival time of 15 min, a 0.05 microl injection produced a labeled area of 5.25 mm(2) at the injection site and a rostrocaudal labeling of 1.7 mm. Increasing the survival time to 60 min, or increasing the injected volume to 0.1 microl, systematically led to a larger labeled area at the injection site (8-12 mm(2)) and to a larger rostrocaudal diffusion (2.0-2.5 mm). Direct quantifications of radioactivity by a high-resolution radioimager validated the OD measures and even indicated a larger muscimol diffusion (up to 3.25 mm). Thus, these data point out that muscimol diffusion after intracerebral microinjection is larger than usually supposed. The relationships between these results and those obtained in behavioral studies are discussed.

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How an animal learns, remembers, and uses information to guide adaptive behavior remains one of the most challenging questions in science today. Much progress was made in the twentieth century, and new tools available to neurobiological investigators have accelerated progress in the new century. Nevertheless, the road has been rocky and progress sometimes impeded by periodic polemic debates at a conceptual level. Retrospective examination of the nature of the divisive issues and how they were (or were not) resolved could help steer a new generation of investigators away from similar pitfalls and impasses. The same applies to scientists from other disciplines, recently joining in the "search for the engram," who might not be aware of the vast literature generated, mainly by psychologists, in the middle decades of the last century. Our purpose here is not to furnish a complete review of this literature, but to provide a historical perspective for some of the unresolved issues that continue to be discussed within the context of the field of neurobiology of memory. For more general reviews, refer to McGaugh (2000) and Dudai (2004).Scientific investigation of memory processes was initiated at the end of the 19th century by psychologists in Germany, Ebbinghaus (1885) and then Müeller and Pilzecker (1900). Their studies of verbal learning and retention in human subjects led them to conclude that a memory trace was formed gradually over time after acquisition and they coined the term consolidation. Contemporary with this were the very influential clinical observations and theoretical elaborations of the French psychiatrist, Ribot (1882). From his studies of amnesic patients, he formulated "La loi de regression," which simply notes that, as memories age, they become more resistant to trauma-induced amnesia. Consolidation and retrograde amnesiaThe first animal model of amnesia is attributed to another psychologist, C.P. Duncan, who in 1945 published a paper entitled "The effect of electroshock convulsions on the maze habit in the white rat" (Duncan 1945). This was followed in 1948 by "Habit reversal deficit induced by electroshock in the rat" (Duncan 1948), culminating with "The retroactive effect of electroshock on learning" (Duncan 1949). In his first studies, Duncan administered an electroconvulsive shock (ECS) after each daily trial in a complex maze and showed an inverse relationship between the speed of learning and the delay between the trial and the amnestic treatment. In his 1949 paper he concluded that his experiments provided direct evidence for Müeller and Pilzecker's hypothesis stating that post-learning neural perseveration was necessary for consolidating memory. ECS disrupted this activity, thereby preventing post-acquisition memory consolidation. In the same year, and quite independently of Duncan's results, Hebb (1949) formalized this old idea that propagating or recurrent impulses of a specific spatio-temporal pattern underlie initial memory. This provided a strong rationale for the use of ECS as an am...