Abstract: Candidate mammalian odorant receptors were first cloned some 6 years ago. The physiological function of these receptors in initiating transduction in olfactory receptor neurons remains to be established. Here, a recombinant adenovirus was used to drive expression of a particular receptor gene in an increased number of sensory neurons in the rat olfactory epithelium. Electrophysiological recording showed that increased expression of a single gene led to greater sensitivity to a small subset of odorants.

Abstract: The goals of this study were to investigate the transmission and possible functions of chemical signals in intragroup communication among ring-tailed lemurs, Lemur catta. In particular, I examined the effects of sex on these processes because sexual selection theory predicts specific functions for chemical signals. I recorded all interactions with 214 scent marks of 11 male and 9 female ring-tailed lemurs during the first 10 min following their deposition. I found that 62% of these scent marks were investigated with a median latency of 30 s and that 89% of investigated scents were also counter-marked by the receiver. The type of focal scent mark (male or female anogenital and male antebrachial mark) had a significant effect on both the timing and type of response. Males investigated and counter-marked female scents more often than vice versa, but significant second-order transitions suggested that the behavior of an animal was not only influenced by the immediately preceding scent mark and that a scent is not completely masked by a counter-mark. There was no evidence for an audience effect, and only social rank of female senders had an effect on receivers. Variation in the response of receivers across reproductive seasons as a function of senders' sex indicated that female scents may function in mate attraction and competition among females, whereas male scents may be primarily used in intrasexual competition. Three main conclusions emerged. First, the exchange of olfactory signals within groups was highly structured and surprisingly efficient. Second, olfactory signals may constitute general mesasages whose transfer is partly controlled by the receiver. Finally, sexual selection theory provides a useful theoretical framework for functional examinations of mammalian olfactory communication.

Abstract: Possible roles of the insect mushroom bodies (corpora pedunculata) in behavior have been debated for nearly 150 years (Dujardin 1850). It took more than a century before some of the hypotheses could be tested experimentally and even then, the means of intervention proved unsatisfactory. Lesions and electrical stimulation in the mushroom bodies (MBs) caused a large variety of behavioral symptoms that were difficult to reconcile with a common function (for review, see Erber et al. 1987). Among the behavioral properties affected by lesions were cocoon spinning in Cecropia larvae (van der Kloot and Williams 1954), the organization of behavioral sequences in bees and locusts (Howse 1974), odor thresholds and optomotor latencies in the cockroach (Drescher 1960), as well as the suppression of locomotor activity in crickets and grasshoppers (Huber 1960). Fortunately, one behavioral impairment has now been consistently found with different lesioning techniques and in different insect species: olfactory learning and memory. First hints indicating that the MBs are required for the retention of odors came from extensive bilateral lesions in bees (Voskresenskaja 1957) and ants (Vowles 1964). Later, Masuhr (1976) applied more confined lesions in the calyces or α-lobes of the honeybee with similar results. Subsequently, he developed a special probe for locally cooling small areas of the bee brain. With this elegant technique he was able to interfere with short-term memory in the antennal lobe, calyces, or α-lobe (Erber et al. 1980). A decade later, two Drosophila mutants with severe structural defects in the MBs, but entirely different etiologies of the mutant defects, were shown to be impaired in olfactory memory (Heisenberg et al. 1985). A further decade later, it became possible to ablate the MBs in wild-type Drosophila by applying a cytostatic drug, hydroxyurea (HU), to the first larval instar (Prokop and Technau 1994). The result was the same—a severe defect in olfactory memory (de Belle and Heisenberg 1994). Recently, Connolly et al. (1996) went a step farther and confined the block to the Kenyon cells by specifically expressing a constitutively activated Gαs protein subunit in these cells. Again, odor retention was specifically impaired. If the expression of the mutated transgene leaves the circuitry of the MB pathway intact, the experiment shows that blocking modulation of the Kenyon cell output synapses is sufficient to impair olfactory memory. The cumulative evidence from hymenopterans and flies leaves little doubt that MBs are involved in olfactory memory. This finding calls to mind the proposal of Hanstrom (1928), suggesting that the MBs may be general association organs. The MBs do receive many types of sensory input (for review, see Erber et al. 1987; Schurmann 1987), and in Drosophila the MBs have been shown recently to be structurally affected by visual experience (Barth and Heisenberg 1997). However, outside the realm of chemoreception little evidence supports Hanstrom’s view. Flies of the mushroom bodies deranged (mbd) mutant stock with severely defective MBs have been shown to remember colors (Heisenberg et al. 1985; Heisenberg 1989). Moreover, mutant mbd as well as mushroom body miniature1 (mbm1) flies are able to reorganize their visuomotor interface in response to inverted coupling in the flight simulator (preliminary data cited in Heisenberg 1989). Here we reinvestigate the question whether the MBs might be involved in visual and other kinds of associative learning and memory besides odor preference conditioning. We take advantage of the HU ablation technique (Prokop and Technau 1994) for the generation of MB-less flies (HU-flies). The HU technique seems particularly suited for studying the role of the MBs in visual behavior because the optic anlagen do not start postembryonic development until after HU treatment (Ito and Hotta 1991). The volume of the adult optic lobes is not affected in HU flies (deBelle and Heisenberg 1994). In the time window of the treatment, in each brain hemisphere only five neuroblasts proliferate. Four of them, the MB neuroblasts, give birth to the postembryonic Kenyon cells, and a fifth one generates neurons of the antennal lobe (Ito and Hotta 1991; Prokop and Technau 1994). In the adult animal, HU treatment leads to the virtually complete absence of MBs and, in addition, to a 30% reduction of the volume of the antennal lobe (de Belle and Heisenberg 1994). In this study we test MB-less flies in six learning paradigms, four of which involve visual orientation. Five are operant and one is a classic form of conditioning. In four paradigms, the animals are tethered in flight; in two paradigms, freely walking flies are tested. Different kinds of reinforcements and various conditioned stimuli are used. In all these situations MB-less flies perform as well as normal ones. The involvement of the MBs in learning and memory seems to be confined to olfaction and possibly taste.

Abstract: ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative illness marked by memory loss and at least one other cognitive disturbance. Early diagnosis of the disease has proved difficult and has therefore been the focus of much research. Apolipoprotein E (ApoE), a protein manufactured and distributed throughout the body, has shown specificity of binding to the βA4 peptide, the primary component in the senile plaques of AD. Furthermore, the ApoE, epsilon 4 (ɛ4) allele, is overrepresented in AD. These two lines of evidence suggest that ApoE, specifically the ɛ4 allele, plays an important role in the development of AD. Further support for this hypothesis appears in neuropsychological data showing cognitive decrements in ostensibly nondemented individuals with the ɛ4 allele, compared to those without the allele. It is also well known that olfaction is compromised in AD. Thus, the purpose of this study was twofold: (1) to examine very early changes in olfactory functioning due to AD and (2) to examine the role of ApoE in olfactory functioning in people at risk for AD by virtue of early cognitive decline. Results demonstrated changes in olfactory threshold the year immediately preceding change in diagnosis from normal control to AD. Also, in individuals with mild cognitive impairment, those with the ApoE ɛ4 allele show poorer thresholds than those without the ɛ4 allele.

Abstract: The sense of smell shows a diminution with age as measured by the University of Pennsylvania Smell Identification Test (UPSIT). To ascertain whether the volumes of the olfactory bulbs and tracts (OBTs) and the temporal lobes (TL) declined in parallel to smell function, we examined 36 individuals from ages 22 to 78 who did not complain of any loss of the sense of smell using magnetic resonance (MR) imaging. The OBT volumes showed an initial increase to the 4th decade of life and then a decrease with increasing age, while the trend in TL volume was not as dramatic. There was no correlation between OBT or TL volumes with unilateral or total UPSIT scores. The normative data by decades can be used to assess the OBTs of cohorts of patients with neurodegenerative disorders that affect olfaction.

Abstract: The olfactory system is one of the nonmotor systems severely affected in Parkinson's disease (PD). Olfactory dysfunction occurs early in the disease process, is independent of disease stage, duration, and treatment. However, olfactory dysfunction appears to be dependent on disease subtype. Olfaction is mildly impaired or preserved in most of the parkinsonism-plus syndromes (PPS). This provides a means of differential diagnosis between typical PD and PPS. Olfactory function is impaired also in familial forms of parkinsonism in which the genetic defect is known. In familial parkinsonism, olfactory function is impaired in both typical PD and PPS phenotypes. Olfactory dysfunction does not appear to be a manifestation of dopamine deficiency. Olfactory dysfunction is also associated with other neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD), as well as with normal aging. The neuropathological changes observed in the olfactory system in PD and other neurodegenerative diseases appear to be disease-specific, raising the possibility that olfactory dysfunction may be the result of a central rather than a peripheral process. The cellular and molecular mechanisms underlying olfactory dysfunction in PD and other neurodegenerative diseases remain unknown.

Abstract: The nitric oxide (NO)–cGMP signaling system is thought to play important roles in the function of the olfactory system in both vertebrates and invertebrates. One way of studying the role of NO in the nervous system is to study the distribution and properties of NO synthase (NOS), as well as the soluble guanylyl cyclases (sGCs), which are the best characterized targets of NO. We study NOS and sGC in the relatively simple and well characterized insect olfactory system of the hawkmoth, Manduca sexta . We have cloned Manduca sexta nitric oxide synthase (MsNOS) and two sGCs (MsGCα1 and MsGCβ1), characterized their basic biochemical properties, and studied their expression in the olfactory system. The sequences of the Manduca genes are highly similar to their mammalian homologs and show similar biochemical properties when expressed in COS-7 cells. In particular, we find that MsGC functions as an obligate heterodimer that is stimulated significantly by NO. We also find that MsNOS has a Ca2+-sensitive NO-producing activity similar to that of mammalian neuronal NOS. Northern and in situ hybridization analyses show that MsNOS and the MsGCs are expressed in a complementary pattern, with MsNOS expressed at high levels in the antennae and the MsGCs expressed at high levels in a subset of antennal lobe neurons. The expression patterns of these genes suggest that the NO–sGC signaling system may play a role in mediating communication between olfactory receptor neurons and projection neurons in the glomeruli of the antennal lobe.

Abstract: Lesions of both dorsal and ventral hippocampus were produced by multiple infusions of the excitotoxin AMPA. Meal patterns recorded before and after lesioning showed no change in total food intake, but a striking behavioral syndrome in which the lesioned rats took smaller meals 2-3 times as frequently and showed a similar change in drinking. In addition, lesioned rats alternated more frequently between feeding and drinking during a single bout of ingestive behavior. There were no group differences in the satiety sequence that followed a meal. In an open field test, lesioned rats showed enhanced locomotion in the periphery and reduced rearing. An olfactory habituation-dishabituation task showed that the lesioned rats investigated olfactory stimuli less but dishabituation to a changed stimulus was normal. The data are discussed in terms of changes in behavioral switching or a possible interoceptive agnosia following hippocampal damage.

Abstract: We conducted 2 studies to determine the importance of several brain systems for remembering odorants in a go/no-go delayed nonmatching-to-sample (DNMTS) task. In Experiment 1, impairments were observed for lesions of pyriform cortex or (to a lesser extent) the lateral internal medullary lamina of thalamus. Lesions of the entorhinal cortex or the mediodorsal (MDn) or the paracentral and centrolateral (PC-CL) thalamic nuclei did not affect DNMTS. In Experiment 2, an impairment comparable to the pyriform lesion was observed for a lesion of the intralaminar nuclei (PC-CL plus the central medial nucleus) but not for a larger lesion of MDn. None of the lesions in either study affected the ability to learn a 2-choice odor discrimination using go/no-go procedures comparable with the DNMTS task.

Abstract: Normal rats and rats with hippocampal system damage were trained on a novel, olfactory version of the transverse-patterning task that involved the concurrent learning and continued performance of 3 partially ambiguous discrimination problems (A+B-, B+C-, C+A-). Animals with lesions of the fornix or perirhinal-entorhinal cortex acquired at least as rapidly as normal rats these problems presented in sequential blocks of trials involving the same stimulus pair. All groups also performed well on an initial test session when the order of stimulus pair presentations was randomized. Normal rats continued to discriminate appropriately in additional testing sessions with trials presented in random order. By contrast, both groups with hippocampal system damage performed poorly in continued random-order testing. These results extend the generality of the deficit in transverse patterning to the olfactory modality and demonstrate that the deficit is equivalent in magnitude after fornix or perirhinal-entorhinal damage. Findings also suggest that the transverse-patterning problem can be acquired transiently without critical hippocampal involvement, although continued performance relies on hippocampal function.

Abstract: To investigate the neural encoding of glutamate (umami) taste in the primate, recordings were made from taste responsive neurons in the cortical taste areas in macaques. Most of the neurons were in the orbitofrontal cortex (secondary) taste area. First, it was shown that there is a representation of the taste of glutamate which is separate from the representation of the other prototypical tastants sweet (glucose), salt (NaCl), bitter (quinine) and sour (HCl). Second, it was shown that single neurons that had their best responses to sodium glutamate also had good responses to glutamic acid. Third, it was shown that the responses of these neurons to the nucleotide umami tastant inosine 5'-monophosphate were more correlated with their responses to monosodium glutamate than to any prototypical tastant. Fourth, concentration response curves showed that concentrations of monosodium glutamate as low as 0.001 M were just above threshold for some of these neurons. Fifth, some neurons in the orbitofrontal region, which responded to monosodium glutamate and other food tastes, decreased their responses after feeding with monosodium glutamate to behavioral satiety, revealing a mechanism of satiety. In some cases this reduction was sensory-specific. Sixth, it was shown in psychophysical experiments in humans that the flavor of umami is strongest with a combination of corresponding taste and olfactory stimuli (e.g., monosodium glutamate and garlic odor). The hypothesis is proposed that part of the way in which glutamate works as a flavor enhancer is by acting in combination with corresponding food odors. The appropriate associations between the odor and the glutamate taste may be learned at least in part by olfactory to taste association learning in the primate orbitofrontal cortex.

Abstract: Purpose: Our goal was to demonstrate that medical therapy in patients with smell loss (hyposmia) that restored olfactory function toward or to normal could be verified and quantitated by functional MRI (fMRI) of brain and that visual representation of these changes could be used to identify these patients. Method: Multislice FLASH MR or echo planar MR brain scans were obtained in four patients with hyposmia in response to three olfactory stimuli both before and after treatment with theophylline. Activation images were derived using correlation analysis, and ratios of brain area activated to total brain area were obtained. Results: Prior to treatment, all patients stated that they could not smell; these losses were confirmed by standard psychophysical tests. At this time, fMRI brain activation in response to odors was significantly less than that measured in normal volunteers and similar to activation measured previously in other patients with a similar type of hyposmia. After treatment, subjective smell function improved in three patients and no improvement occurred in one; results were confirmed by psychophysical tests. In each patient in whom smell acuity improved, brain activation in response to each odor increased in each section and mean activation increased significantly for each odor. Activation increased in all regions previously associated with olfactory stimulation and was particularly apparent in orbitofrontal cortex, frontal lobe component of cingulate gyri, temporal lobe gyri, and hippocampus. There also was consistent activation in superior, middle, and inferior frontal lobe gyri. There were no changes in brain activation after treatment in the patient in whom smell did not improve. Conclusion: These results demonstrate that theophylline is an effective therapeutic agent to correct hyposmia in some patients with smell loss. These changes have been documented by fMRI brain scans using olfactory stimuli. This is the first study in which this type of objective improvement following medical treatment has been demonstrated in patients with hyposmia.

Abstract: We use classical conditioning of the honeybee (Apis mellifera) proboscis extension reflex with a visual (A) and an olfactory (X) conditioned stimulus in a blocking paradigm. Typically, learning about one element (X) of a compound (AX) is decreased (blocked) if the other component (A) has previously been rewarded alone. Our results show that visual pretraining did not produce blocking in honeybees: instead, forward pairings of A with a reward increased subsequent learning about X relative to a backward pairing control. This finding violates the independence assumption, which holds that elements of inter-modal compound stimuli change associative strength independently of each other. Furthermore, it is at odds with common theories of conditioning that predict blocking and assume that the elements of a compound stimulus rely on one common internal reinforcing signal. Taking the functional anatomy of the honeybee brain into account, we suggest that vision and olfaction may not rely on the same internal reinforcing signal; compound interactions might thus reflect the wiring of the honeybee nervous system and the biological significance of different sensory modalities during natural behaviour.

Abstract: Objectives: Define the presence and distribution of glucocorticoid receptors (GRs) within the olfactory mucosa in order to assess potential physiologic and pathophysiologic effects of these hormones on olfaction. Study Design: The olfactory mucosa was harvested from adult male rats and guinea pigs. Kidney tissue was utilized as a known positive control. Methods : The techniques of reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemistry were utilized to examine the expression of GR mRNA and protein. To assure the presence of olfactory mucosa in the nasal tissue samples, RT-PCR was utilized to identify the olfactory marker protein (OMP). Results: The presence of GR mRNA was confirmed in both the olfactory mucosa and kidney. GR-like immunoreactivity associated with the olfactory epithelium was greatest at the apical surface, a position corresponding to the dendrites, knobs, and cilia of olfactory receptor neurons, as well as the supranuclear region of sustentacular cells. Weaker GR-like immunoreactivity was associated with the region of the cell bodies of the olfactory receptor neurons. Within the lamina propria, acinar cells of the Bowman's glands and olfactory nerve bundles were intensely immunoreactive. Conclusions: The presence of GR mRNA and protein within the olfactory mucosa is consistent with a functional role for glucocorticoid hormones in the systemic regulation of olfaction. Furthermore, these studies suggest that corticosteroid medications may have direct effects on the cells of the olfactory mucosa in the pathologic state. The potential mechanisms whereby these hormones may act are discussed.

Abstract: It has been proposed that memory for odors does not have a short-term (or working) memory system. The distinction between short- and long-term memory in other sensory modalities has been generally supported by three main lines of evidence: capacity differences between the proposed systems, evidence of differential coding, and differential memory losses in neuropsychological patients. The present paper examines these issues in an effort to establish a similar distinction for the memory of olfactory stimuli. Each of these lines of evidence is examined in relation to the literature on olfactory memory. Based on this examination, it seems that there is at least preliminary support from each of these lines of evidence to advocate a distinction between a long- and short-term memory for olfactory stimuli. Emphasis is placed upon the qualitative similarity of olfactory memory to other memory systems. This similarity is further highlighted through an examination of the literature pertinent to serial position effects in memory for olfactory stimuli.

Abstract: OBJECTIVE: Abnormalities of olfactory identification ability have been proposed as a marker of cerebral dysfunction in schizophrenia. The authors studied the potential role of genetic factors in olfactory dysfunction by assessing monozygotic twins discordant for schizophrenia and matched comparison subjects. METHOD: The subjects were 12 pairs of monozygotic twins discordant for schizophrenia and 12 healthy subjects matched for sex and age. Each subject completed the University of Pennsylvania Smell Identification Test. RESULTS: The combined twin group scored significantly lower on smell identification than did the comparison group. The affected and unaffected twin groups did not differ from each other. CONCLUSIONS: Genetic factors may contribute to cerebral dysfunction as assessed by olfactory identification ability. (Am J Psychiatry 1998; 155:134–136)

Abstract: Following recovery from olfactory nerve transection, animals regain their ability to discriminate between odors. Odor discrimination is restored after new neurons establish connections with the olfactory bulb. However, it is not known if the new connections alter odor quality perception. To address this question, 20 adult hamsters were first trained to discriminate between cinnamon and strawberry odors. After reaching criterion (≥90% correct response), half of the animals received a bilateral nerve transection (BTX) and half a surgical sham procedure. Animals were not tested again until day 40, a point in recovery when connections are re-established with the bulb. When BTX animals were tested without food reinforcement, they could not perform the odor discrimination task. Sham animals, however, could discriminate, demonstrating that the behavioral response had not been extinguished during the 40 day period. When reinforcement was resumed, BTX animals were able to discriminate between cinnamon and strawberry after four test sessions. In addition, their ability to discriminate between these two familiar odors was no different than that of BTX and sham animals tested with two novel odors, baby powder and coffee. These findings suggest that, after recovery from nerve transection, there are alterations in sensory perception and that restoration of odor quality discrimination requires that the animal must again learn to associate individual odor sensations with a behavioral response.