Tim Otto

Complementary roles of the orbital prefrontal cortex and the perirhinal-entorhinal cortices in an odor-guided delayed-nonmatching-to-sample task

Continuing efforts toward designing odor-guided tasks for rats that are similar in memory demands to tasks used typically with primates have resulted in the development of a continuous delayed-nonmatching-to-sample (cDNM) task that is guided by olfactory stimuli. The results indicate that normal subjects acquire the cDNM task rapidly and that subsequent performance deteriorates with increases in memory delay or interitem interference. Moreover, different aspects of cDNM performance were shown to be differentially sensitive to selective lesions of the orbitofrontal and parahippocampal areas. Orbitofrontal cortex lesions disproportionately impaired cDNM acquisition; delay performance was impaired only under conditions of elevated levels of interitem interference. Combined perirhinal and entorhinal cortical lesions had no effect on cDNM acquisition but impaired cDNM performance at longer delays across all levels of interference. Fornix lesions did not impair either acquisition of cDNM or subsequent performance across long delays and increased interference. This pattern of impaired and spared capacities is similar to that observed in monkeys after lesions of analogous areas and is consistent with the notion that the prefrontal cortical system contributes preferentially to learning general task rules such as the nonmatching rule that is inherent in cDNM, whereas the perirhinal and entorhinal cortical areas are involved in the intermediate-term maintenance of memories for specific information.

Entorhinal-perirhinal lesions impair performance of rats on two versions of place learning in the Morris water maze.

The effects of entorhinal-perirhinal lesions in rats were studied with 2 versions of a place learning task in the Morris water maze. These lesions impaired performance on a multiple-trial task (3 days of 6 trials and a probe trial). This assessment was followed by a task in which rats were repeatedly trained to find novel locations with a variable delay (30 s or 5 min) imposed between each sample trial and retention test. Entorhinal-perirhinal damage produced a delay-dependent deficit in spatial memory: Rats with lesions were impaired at the 5-min delay relative to the control group and to their own performance at 30 s. These findings are discussed in relationship to memory impairment after entorhinal damage and spatial learning deficits observed after hippocampal damage.

Altered Social Behavior in Pituitary Adenylate Cyclase-Activating Polypeptide Type I Receptor-Deficient Mice

The olfactory bulb plays a critical role in odor discrimination and in processing olfactory cues controlling social behavior in mammals. Given that the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1) is highly expressed in the olfactory bulb, we examined its role in regulating olfaction and social investigation. We found that olfactory detection of nonsocial stimuli was similar in PAC1-deficient mice and wild-type (WT) littermates. In contrast, PAC1-deficient mice displayed markedly abnormal social behaviors. PAC1-deficient mice exhibited a faster decrease in social investigation after repeated exposure to social cues or ovariectomized female urine compared with WT mice. Moreover, PAC1-deficient females exhibited delayed affiliative behavior when housed with novel males, and PAC1-deficient males displayed excessive sexual mounting toward both females and males as well as reduced aggression and increased licking and grooming toward intruder males. In aggregate, these results uncover PAC1 signaling as an important factor in the development and/or functioning of neural pathways associated with pheromone processing and the regulation of social interactions in mice. In turn, these studies raise the potential clinical relevance of PACAP signaling dysfunctions in neuropsychiatric disorders characterized by social reciprocity impairments such as autism spectrum disorders.

The Importance of Having Arc: Expression of the Immediate-Early Gene Arc Is Required for Hippocampus-Dependent Fear Conditioning and Blocked by NMDA Receptor Antagonism

Long-lasting, experience-dependent changes in synaptic strength are widely thought to underlie the formation of memories. Many forms of learning-related plasticity are likely mediated by NMDA receptor activation and plasticity-related gene expression in brain areas thought to be important for learning and memory, including the hippocampus. Here, we examined the putative role of activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene (IEG) whose expression is tightly linked to the induction and maintenance of some forms of neuronal plasticity, in hippocampus-dependent and hippocampus-independent forms of learning. The extent to which learning-induced Arc expression may depend on NMDA receptor activation was also assessed. First, we observed an increase in Arc gene and protein products in both dorsal hippocampus (DH) and ventral hippocampus (VH) of male Sprague Dawley rats after hippocampus-dependent trace and contextual fear conditioning, but not after hippocampus-independent delay fear conditioning. Specific knockdown of Arc using antisense oligodeoxynucleotides (ODNs) in DH or VH attenuated the learning-related expression of Arc protein, and resulted in a dramatic impairment in trace and contextual, but not delay, fear conditioning. Finally, pretraining infusions of the NMDA receptor antagonist APV into the DH or VH blocked the learning-induced enhancement of Arc in a regionally selective manner, suggesting that NMDA receptor activation and Arc translation are functionally coupled to support hippocampus-dependent memory for fear conditioning. Collectively these results provide the first evidence suggesting that NMDA receptor-dependent expression of the IEG Arc in both DH and VH likely underlies the consolidation of a variety of forms of hippocampus-dependent learning.

Analysis of aversively conditioned learning and memory in rats recovered from pyrithiamine-induced thiamine deficiency

Rats that had recovered from pyrithiamine-induced thiamine deficiency (PTD) were trained on tasks motivated by escape from mild footshock. On postmortem examination, the PTD model showed two consistent lesions: a bilaterally symmetrical lesion of the medial thalamus, which was centered on the internal medullary lamina (IML), and a lesion centered on the medial mammillary nuclei. PTD rats with IML lesions were impaired in learning a spatial nonmatching-to-sample (NMTS) task that was mastered without error by controls and PTD animals without IML lesions. These same animals were able to perform as well as controls on discrimination tasks based on either place or visual (light-dark) cues, although they made more errors than controls in reaching criterion in the initial place discrimination problem. These findings are consistent with findings from appetitively motivated tasks that PTD rats with IML lesions have an impaired capacity for working memory but not for reference memory.

LTP and memory: can we enhance the connection?

ploration-induced effects are short lived, leading to the name shortterm exploratory modulation (STEM). In addition, while both LTP and STEM are characterized by an increased EPSP, they differ with respect to the evoked population spike, which is enhanced in LTP, and reduced in STEM. However, this discrepancy was interpreted as STEM involving the summed strengthening of synapses on a select few excitatory cells and on many inhibitory cells that produce a feedforward inhibition 5. These exciting discoveries, combined with replications of STEM, including controls for EEG state and locomotion 5, caused many of us to embrace the notion that STEM might reflect specific information processing. Enthusiasm was further raised by a neuro

Odor-guided learning and memory in rats: is it ‘special’?

the first 20 trials of each problem after having learned no more than four such problems previously. Rapid progressive improvement is not a special feature of olfactory learning. There remains one feature of olfactory learning that might prompt us to allow it some special status, and ironically this is found in the work of Reid and Morris 3 themselves. It is their finding that serial reversal improvement fails to occur. Such improve- ment emerges quite readily when rats are trained on an analogous visual discrimination 3. One reason for this improvement, it has been suggested, is that the rats come to restrict attention to the relevant stimuli, to abandon position habits, and so on, an interpret- ation that makes Reid and Morriss failure to find the effect all the more puzzling since it is just these processes that they suggest might generate the improvement they observe in the olfactory learning-set procedure. I have no solution to this enigma. All I can do is express the hope that further research will clarify the issue of what conditions are necessary for serial reversal improvement in ol- factory learning; also, given the current state of confusion on this issue, to urge caution about taking the Reid and Morris result as a convincing demon- stration that olfactory learning is in some way special.

Spectral responsivity of the white–black channel

Three subjects viewed, foveally and monocularly, a monochromatic test field of 0.6-deg diameter that was surrounded by a white annulus of 0.6-deg inner diameter and 4.5-deg outer diameter. The wavelength of the central test field was varied in steps of 10 nm from 440 to 640 nm, and its luminance was set to 100 Td. Center and surround were flashed together for 2 sec every 4 sec. The subjects adjusted the luminance of the surround so that the central field was perceived as having equal amounts of whiteness and blackness. The luminance of the surround required for this balance point varied with the wavelength of the test field in a manner that closely resembled a heterochromatic brightness matching function obtained under similar conditions. Control experiments ruled out the possibility that the subjects were making brightness matches between center and surround fields. Additional evidence was provided suggesting that the spectral responsivity of the putative white-black channel is best represented by a photopic spectral sensitivity curve based on equal brightness.

Colors of monochromatic lights that vary in contrast-induced brightness

Using a color-naming procedure, two subjects described monochromatic lights, ranging from 450 to 630 nm, that were surrounded by perceptually unique-white fields of variable retinal illuminance. The test fields were 0.6 deg and 10, 100, or 1,000 Td. The surrounds, which were 4.5 deg in outer diameter, ranged from 0 to approximately 31,000 Td. From the resulting color-naming functions, equal-hue contours were derived, with surround intensity plotted against wavelength, for the spectral unique hues and the binary hues blue-green, green-yellow, and yellow-red. The wavelengths for unique blue, unique yellow, and blue-green were essentially invariant with changes in surround intensity. The spectral locus for unique green was also invariant at higher test-field intensities, but, at lower levels, it generally shifted toward shorter wavelengths as surround intensity increased. Nonmonotonic shifts were found for green-yellow and yellow-red. The contrast and the wavelength requirements for the color brown were nearly invariant with the changes of test-field intensity. Over the full range of surround intensities, subjects described the test fields as consisting of one or two hues plus white or black, depending on the surround level, but never (except for one subject at the lowest test-field intensity) white and black simultaneously and cospatially. This opponent aspect of black and white was compared with that associated with the chromatically opponent processes.

The Hippocampus and the Sense of Smell

Brodal, in a 1947 review from which we boldly borrow the title of the present paper, outlined some of the critical evidence that ultimately led to the demise of the notion that the hippocampus was a part of the olfactory brain, or “rhinencephalon” as it was called according to the prevailing view of the time. Since then it has become abundantly clear that the hippocampus processes information from many input sources (cf. Deacon et al., 1983). Nevertheless, converging data from neuroanatomical, physiological, and behavioral studies indicate that the olfactory system projects heavily onto and has especially immediate access to the hippocampal system, suggesting that the olfactory-hippocampal pathway may be particularly useful for explorations of sensory-limbic interactions leading to the higher order coding of perceptual information. As will be described below, the intimate anatomical associations between the olfactory and hippocampal systems are paralleled by 1) the critical role played by the hippocampal system in odor-guided learning and memory, 2) the strong influence of olfactory processing over the physiological activity in the hippocampus both at the level of rhythmic EEG activity and at the level of neuronal firing patterns, and 3) the role these physiological processes may play in the induction of synaptic plasticity supporting memory formation. Thus, in the spirit of a “renaissance of the rhinencephalon” (Macrides, 1977), we will argue that olfaction is a particularly advantageous model system for studies of “sensory” processing by the hippocampus across behavioral, neuronal, and synaptic levels of analysis. Our data on studies at each of these levels of analysis will be discussed in turn (see also Otto and Eichenbaum, 1992b).