Women Want Choices: Opinions from the Share.Learn.Shape Global Internet Survey About Multipurpose Prevention Technology (MPT) Products in Development.

Women need multipurpose prevention technologies (MPTs) to simultaneously prevent sexually transmitted infections (STIs), including HIV, with or without contraception. User feedback early in product development is critical for maximizing uptake and continuation. Our global online survey (April 2017-December 2018) explored women's opinions about MPT formulations in development (e.g., fast-dissolving vaginal inserts, vaginal films, intravaginal rings, injectables, implants), preferences for long-acting or "on-demand" methods, and interest in a contraceptive MPT versus products for HIV/STI prevention alone. Of the 630 women in our final analysis (mean 30 years old; range 18-49), 68% were monogamous, 79% completed secondary education, 58% had ≥ 1 child, 56% were from sub-Saharan Africa and 82% preferred a cMPT versus HIV/STI prevention alone. There were no clear preferences for any specific product or product type (long-acting, on-demand, daily). No single product will appeal everyone, however, adding contraception is likely to increase uptake of HIV/STI prevention methods for most women.

RESUMEN: Las mujeres necesitan tecnologías de prevención multipropósito (TPM) para prevenir simultáneamente las infecciones de transmisión sexual (ITS), incluido el VIH, con o sin anticoncepción. Las opiniones de los usuarios cuando un producto comienza a desarrollarse son fundamentales para maximizar la adopción y continuación de dicho producto. Nuestra encuesta global realizada en internet (abril de 2017­diciembre de 2018) exploró las opiniones de las mujeres sobre diferentes fórmulas o dispositivos de TPM que se están desarrollando (ej., insertos vaginales de disolución rápida, láminas vaginales, anillos intravaginales, inyectables, implantes). En esta encuesta se indagó acerca de las preferencias en términos de período de acción (prolongado o breve) y propósito del uso (anticonceptivo, productos para la prevención del VIH/ITS, o ambos). De las 630 mujeres (media de 30 años; rango 18­49) en el análisis final, el 68% eran monógamas, el 79% completaron la educación secundaria, el 58% tenían ≥ 1 hijo, el 56% eran del África subsahariana y el 82% preferían una TPM con componente anticonceptivo en vez de un producto para la prevención de VIH/ITS exclusivamente. No hubo preferencias claras por ningún producto o tipo de producto específico (de acción prolongada, de acción breve, de uso diario). Ningún producto por sí solo logró abarcar todas las preferencias; sin embargo, es probable que la inclusión de métodos anticonceptivos en una TPM aumente el uso de métodos de prevención del VIH/ITS en la mayoría de las mujeres.

Feasibility of yoga as a complementary therapy for patients with type 2 diabetes: The Healthy Active and in Control (HA1C) study.

OBJECTIVES: This study:Healthy Active and in Control (HA1C), examined the feasibility and acceptability of yoga as a complementary therapy for adults with Type-2 Diabetes (T2DM). DESIGN: A 2-arm randomized clinical trial comparing Iyengar yoga with a supervised walking program. SETTING: Hospital based gym-type facility and conference rooms. INTERVENTIONS: Participants were randomized to a 12-week program of either; (1) a twice weekly Iyengar yoga, or (2) a twice-weekly program of standard exercise (SE). MAIN OUTCOME MEASURES: Primary outcomes assessed feasibility and acceptability, including enrollment rates, attendance, study completion, and participant satisfaction. Secondary outcomes included HbA1c, physical activity, and measures of diabetes-related emotional distress, self-care and quality of life (QOL). Assessments were conducted at baseline, end of treatment, 6-months and 9-months post-enrollment. RESULTS: Of 175 adults screened for eligibility, 48 (30 women, 18 men) were eligible and enrolled. The most common reasons for ineligibility were orthopedic restrictions, HbA1c levels <6.5 and BMI > 42. Session attendance was high (82% of sessions attended), as was follow-up completion rates (92%). Program satisfaction rated on a 5-point scale, was high among both Yoga (M = 4.63, SD = 0.57) and SE (M = 4.77, SD = 0.52) participants. Overall 44 adverse events (26 Yoga, 18 SE) were reported. Of these, six were deemed "possibly related" (e.g., neck strain, back pain), and 1 "probably related" (ankle pain after treadmill) to the study. Yoga produced significant reductions in HbA1c. Median HbA1c at 6 months was 1.25 units lower for Yoga compared to SE (95% CI: -2.54 -0.04). Greater improvements in diabetes self-care, quality of life, and emotional distress were seen among Yoga participants than among SE participants. Increases in mindfulness were seen in Yoga but not in SE. CONCLUSIONS: The yoga intervention was highly feasible and acceptable, and produced improvements in blood glucose and psychosocial measures of diabetes management.

Vaginal film for prevention of HIV: using visual and tactile evaluations among potential users to inform product design.

Topical prevention of HIV and other STIs is a global health priority. To provide options for users, developers have worked to design safe, effective and acceptable vaginal dissolving film formulations. We aimed to characterize user experiences of vaginal film size, texture and color, and their role in product-elicited sensory perceptions (i.e. perceptibility), acceptability and willingness to use. In the context of a user-centered product evaluation study, we elicited users' 'first impressions' of various vaginal film formulation designs via visual and tactile prototype inspection during a qualitative user evaluation interview. Twenty-four women evaluated prototypes. Participants considered size and texture to be important for easy insertion. Color was more important following dissolution than prior to insertion. When asked to combine and balance all properties to arrive at an ideal film, previously stated priorities for individual characteristics sometimes shifted, with the salience of some individual characteristics lessening when multiple characteristics were weighted in combination. While first impressions alone may not drive product uptake, users' willingness to initially try a product is likely impacted by such impressions. Developers should consider potential users' experiences and preferences in vaginal film design. This user-focused approach is useful for characterizing user sensory perceptions and experiences relevant to early design of prevention technologies.

A mixed methods approach to improving recruitment and engagement of emerging adults in behavioural weight loss programs.

OBJECTIVE: Emerging adults ages 18-25 are at high risk for obesity, but are markedly underrepresented in behavioural weight loss (BWL) programs and experience lower engagement and retention relative to older adults. PURPOSE: To utilize a mixed methods approach to inform future efforts to effectively recruit and engage this high-risk population in BWL programs. METHODS: We used a convergent parallel design in which quantitative and qualitative data were given equal priority. Study 1 (N = 137, age = 21.8 + 2.2, BMI = 30.1 + 4.7) was a quantitative survey, conducted online to reduce known barriers and minimize bias. Study 2 (N = 7 groups, age = 22.3 + 2.2, BMI = 31.5 + 4.6) was a qualitative study, consisting of in person focus groups to gain greater depth and identify contextual factors unable to be captured in Study 1. RESULTS: Weight loss was of interest, but weight itself was not a central motivation; an emphasis on overall lifestyle, self-improvement and fitness emerged as driving factors. Key barriers were time, motivation and money. Recruitment processes should be primarily online with messages tailored specifically to motivations and preferences of this age group. Preferences for a program were reduced intensity and brief, hybrid format with some in-person contact, individual level coaching, experiential learning and peer support. Key methods of promoting engagement and retention were autonomy and choice, money and creating an optimal default. CONCLUSIONS: An individually tailored lifestyle intervention that addresses a spectrum of health behaviours, promotes autonomy and emphasizes activity and fitness may facilitate recruitment and engagement in this population better than traditional BWL protocols.

A role for neurotrophin-3 in targeting developing cholinergic axon projections to cerebral cortex.

This study examined the relationship between expression of neurotrophin-3 (NT-3) and the ingrowth of cholinergic axonal projections in cerebral cortex. Patterns of expression of NT-3 (defined by beta-galactosidase reporter expression in heterozygous offspring of transgenic NT-3(lacZneo/+) mice) revealed that limbic cortical regions (including frontal, cingulate, and insular cortex, as well as the dentate gyrus) express NT-3 and that these cortical regions receive early and relatively dense cholinergic axons (stained for acetylcholinesterase, AChE). Using the dentate gyrus as a model system, studies revealed that expression of the NT-3 reporter parallels, and precedes by approximately 2 days, the ingrowth of AChE positive cholinergic axons. Studies of forebrain organotypic slice cultures demonstrate that basal forebrain-derived cholinergic axons extend into cortical regions in a pattern that mimics the pattern of expression of the NT-3 reporter. Similarly, chimeric co-cultures, combining wild type septum with a slice of hippocampus from heterozygous NT-3(lacZneo/+) mice, demonstrate that cholinergic axons grow into regions of the dentate gyrus that express the NT-3 reporter. Hemisphere slice cultures made from NT-3 knockout mice reveal cholinergic axonal growth into cortex, but these axons do not form the regional pattern characteristic of slice cultures made from wild type or heterozygous NT-3(lacZneo/+) mice. Further, chimeric co-cultures made using slices of wild type septum combined with slices of hippocampus from NT-3 knockout mice demonstrate robust cholinergic axonal growth into the hippocampus, but the cholinergic axons do not form the characteristic preterminal pattern associated with the dentate gyrus. Slice cultures from limbic cortical tissue from the NT-3 null mice do not display exaggerated levels of cell death. In aggregate, these data support the hypothesis that expression of NT-3 by cortical neurons serves to attract basal forebrain cholinergic projections to their target cells in cerebral cortex.

Deafferentation-induced increases in hippocampal insulin-like growth factor-1 messenger RNA expression are severely attenuated in middle aged and aged rats.

Deafferentation of the adult rat dentate gyrus induces reactive axonal growth by surviving afferent systems. In middle aged and aged rats, axonal sprouting is delayed and reduced relative to young adults. The cause for this age-related decline is not known, but it may reflect a decrement in trophic signals which initiate sprouting. Insulin-like growth factor-1 may play a role in sprouting because it (i) promotes axonal growth, (ii) is expressed at elevated levels by microglia just prior to sprouting onset, and (iii) is expressed with better spatiotemporal correspondence to hippocampal sprouting than other trophic factors examined. The present study used in situ hybridization to evaluate the influence of age on deafferentation-induced insulin-like growth factor-1 messenger RNA expression in the dentate gyrus. Messenger RNA levels were markedly elevated 4 days after an entorhinal cortex lesion at 3 months of age. Comparable lesions at 12 months did not significantly increase labeling whereas lesions at 18-26 months caused only a modest increase at 8 days postlesion. These data demonstrate that deafferentation induces more modest and delayed increases in insulin-like growth factor-1 expression in middle aged and aged rats than in young adults. The loss of reactive insulin-like growth factor-1 expression at ages exhibiting an attenuated sprouting response supports (i) an association between insulin-like growth factor-1 and sprouting and (ii) the possibility that impairments in the expression of this factor contributes to reduced axonal plasticity with age.

Astroglial ciliary neurotrophic factor mRNA expression is increased in fields of axonal sprouting in deafferented hippocampus.

Evidence that ciliary neurotrophic factor promotes axonal sprouting and regeneration in the periphery raises the possibility that this factor is involved in reactive axonal growth in the brain. In situ hybridization was used in the present study to determine whether ciliary neurotrophic factor mRNA expression is increased in association with axonal sprouting in deafferented adult rat hippocampus. In untreated rats, ciliary neurotrophic factor cRNA labeling density was high in the olfactory nerve, pia mater, and aspects of the ventricular ependyma and was relatively low within areas of white matter (fimbria, internal capsule) and select neuronal fields (hippocampal cell layers, habenula). After an entorhinal cortex lesion, hybridization was markedly increased in fields of anterograde degeneration, including most prominently the ipsilateral dentate gyrus outer molecular layer and hippocampal stratum lacunosum moleculare. Labeling in these fields was increased by 3 days postlesion, was maximal at 5 days, and returned to normal levels by 14 days. Double labeling demonstrated that, in both control and experimental tissue, ciliary neurotrophic factor mRNA was colocalized with glial fibrillary acidic protein immunoreactivity in astroglia, but it was not colocalized with markers for oligodendrocytes or microglia. These results demonstrate that astroglial ciliary neurotrophic factor expression is increased in fields of axonal and terminal degeneration and that increased expression is coincident with 1) increased insulin-like growth factor-1 and basic fibroblast growth factor expression and 2) the onset of reactive axonal growth. The synchronous expression of these glial factors in fields of deafferentation suggests the possibility of additive or synergistic interactions in the coordination of central axonal growth.

NMDA-receptor modulation of lateral inhibition and c-fos expression in olfactory bulb.

Olfactory bulb primary output neurons, mitral/tufted cells, are glutamatergic and excite inhibitory interneurons, granule cells, by activation of both alpha-amino-3-hydroxy-5-methyl-ioxazole-4-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors. The data presented here demonstrate that the NMDA antagonists MK-801 and CGP39551, but not ketamine, significantly enhanced expression of c-fos mRNA by mitral cells as measured by in situ hybridization. All three antagonists significantly reduced mitral/tufted cell excitation of granule cells as measured with extracellular field potentials following antidromic stimulation of the lateral olfactory tract (LOT). In turn, the NMDA antagonists significantly reduced granule cell mediated feedback inhibition of mitral/tufted cells, as measured with field potential recordings of paired-pulse LOT stimulation, suppression of mitral/tufted cell single-unit spontaneous activity following LOT stimulation, and intracellularly recorded IPSP amplitude in mitral/tufted cells following LOT stimulation. While there was not a perfect correlation between the effects of the NMDA antagonists on c-fos mRNA expression and on inhibition, the results suggest that disinhibition of mitral/tufted cells accounts for the observed enhancement in c-fos mRNA expression induced by NMDA receptor antagonists.

Odors increase Fos in olfactory bulb neurons including dopaminergic cells.

Neuronal activity may lead to long lasting changes in cell phenotype through induction of genes such as c-fos which encode transcriptional regulatory factors. Odor-activated olfactory bulb cells exhibit increases in c-fos mRNA expression. The present study examined whether odor stimulation of awake rats also leads to increases in Fos protein in these cells. The phenotype of Fos-immunoreactive cells was partially characterized using double-immunoperoxidase staining. Odor exposure increased Fos-immunoreactivity (IR) in specific sets of olfactory bulb neurons. Fos-IR was not co-localized with IR for glial fibrillary acidic protein, but was co-localized with tyrosine hydroxylase (TH)-IR in a subpopulation of dopaminergic neurons, suggesting that bulbar TH expression may be regulated in part by a Fos mechanism.

Functional mapping of odor-activated neurons in the olfactory bulb.

Induction of immediate-early gene expression, in particular c-fos, can be used to map neural activity in many brain areas, including the olfactory system. By making use of the resolution provided by cellular localization of c-fos mRNA or Fos protein, those neurons activated by a particular odor stimulus can be identified. Odor presentation to awake rats increases c-fos expression by bulb neurons located in discrete portions of the glomerular layer and in the underlying mitral and granule cell layers. The translaminar distribution of co-ordinately activated cells corresponds to the 'functional unit' predicted by the synaptic organization of the bulb, and the distribution of these units throughout the bulb as a whole differs for different odors. The bulbar pattern of activity is spatially altered by changes in odor intensity and during the course of postnatal development. These findings support the idea that distributed patterns of odor-induced neuronal activity contribute to the encoding of olfactory information. Moreover, the role of c-fos in the transcriptional regulation of other genes suggests a mechanism whereby odor experience can lead to long-term changes in the olfactory system.

Insulin-like growth factor-1 mRNA is increased in deafferented hippocampus: spatiotemporal correspondence of a trophic event with axon sprouting.

Deafferentation is known to induce axonal sprouting in adult brain, but the signals that direct this response are not understood. To evaluate the possible roles of insulin-like growth factor-1 (IGF-1) and basic fibroblast growth factor (bFGF) in central axonal sprouting, the present study used in situ hybridization to evaluate IGF-1 and bFGF mRNA expression in entorhinal deafferented rat hippocampus. Alternate tissue sections were processed for Fink-Heimer impregnation of axonal degeneration, Bandeiraea simplicifolia (BS-1) labeling of microglia, and glial fibrillary acidic protein immunocytochemistry. In control hippocampus, IGF-1 mRNA was localized to a few neurons, with no labeled cells in the dentate gyrus molecular layer; bFGF cRNA hybridization was diffuse in dendritic fields but was dense in CA2 stratum pyramidale. Both mRNA species were increased by deafferentation. The distribution of elevated IGF-1 mRNA corresponded precisely to fields of axonal degeneration and was greatest in the dentate gyrus outer molecular layer and stratum lacunosum moleculare. In these fields, IGF-1 mRNA was elevated by 2 days, reached maximal levels at 4 days, and declined by 10 days postlesion. Double labeling revealed that the majority of IGF-1 cRNA-labeled cells were microglia. In deafferented hippocampus, bFGF mRNA was broadly increased across fields both containing and lacking axonal degeneration. In the dentate, bFGF mRNA levels peaked at 5 days postlesion and remained elevated through 14 days. These results demonstrate that reactive microglia within deafferented hippocampal laminae express IGF-1 mRNA just prior to and during the period of reactive axonal growth and suggest that IGF-1 plays a role in directing the sprouting of spared afferents into these fields.

Focal 2-DG uptake persists following olfactory bulb lesions.

Exposure of rats to different odors produces spatially distinct patterns of 14C-2-deoxyglucose uptake (2-DG) in the glomerular layer of the main olfactory bulb. However, lesions of specific regions of the bulb that reliably contain 2-DG foci reportedly do not impair the ability of rats to perform olfactory-guided behaviors, suggesting that the lesioned olfactory bulb retains odor-responsiveness. Because the absence of focal 2-DG incorporation in lesioned olfactory bulbs has not been verified by 2-DG autoradiography, it cannot be concluded that focal responses in the olfactory bulb do not contribute to the encoding of olfactory information. To examine the effects of bulb lesions on 2-DG uptake in the olfactory bulb, we placed lesions in specific regions of the bulb that reliably contain 2-DG foci. We then exposed rats to odors 3 or 6 weeks later to determine if the lesions effectively eliminated focal 2-DG uptake in these bulbs. The results indicate that lesioned olfactory bulbs contain focal regions of 2-DG uptake in response to odor stimulation.

Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs.

Studies of the trophic activities of brain-derived neurotrophic factor and neurotrophin-3 indicate that both molecules support the survival of a number of different embryonic cell types in culture. We have shown that mRNAs for brain-derived neurotrophic factor and neurotrophin-3 are localized to specific ventral mesencephalic regions containing dopaminergic cell bodies, including the substantia nigra and ventral tegmental area. In the present study, in situ hybridization with 35S-labeled cRNA probes for the neurotrophin mRNAs was combined with neurotoxin lesions or with immunocytochemistry for the catecholamine-synthesizing enzyme tyrosine hydroxylase to determine whether the dopaminergic neurons, themselves, synthesize the neurotrophins in adult rat midbrain. Following unilateral destruction of the midbrain dopamine cells with 6-hydroxydopamine, a substantial, but incomplete, depletion of brain-derived neurotrophic factor and neurotrophin-3 mRNA-containing cells was observed in the ipsilateral substantia nigra pars compacta and ventral tegmental area. In other rats, combined in situ hybridization and tyrosine hydroxylase immunocytochemistry demonstrated that the vast majority of the neurotrophin mRNA-containing neurons in the substantia nigra and ventral tegmental area were tyrosine hydroxylase immunoreactive. Of the total population of tyrosine hydroxylase-positive cells, double-labeled neurons constituted 25-50% in the ventral tegmental area and 10-30% in the substantia nigra pars compacta, with the proportion being greater in medial pars compacta. In addition, tyrosine hydroxylase/neurotrophin mRNA coexistence was observed in neurons in other mesencephalic regions including the retrorubral field, interfascicular nucleus, rostral and central linear nuclei, dorsal raphe nucleus, and supramammillary region. The present results demonstrate brain-derived neurotrophic factor and neurotrophin-3 expression by adult midbrain dopamine neurons and support the suggestion that these neurotrophins influence dopamine neurons via autocrine or paracrine mechanisms. These data raise the additional possibility that inappropriate expression of the neurotrophins by dopaminergic neurons could contribute to the neuropathology of disease states such as Parkinson's disease and schizophrenia.

Cellular localization of transforming growth factor-alpha mRNA in rat forebrain.

The cellular localization of transforming growth factor-alpha (TGF alpha) mRNA in juvenile and adult rat forebrain was examined using in situ hybridization with a 35S-labeled cRNA probe. TGF alpha cRNA-labeled neuronal perikarya were distributed across many forebrain regions including the olfactory bulb, caudate-putamen, nucleus accumbens, olfactory tubercle, ventral pallidum, amygdala, hippocampal stratum granulosum and CA3 stratum pyramidale, and piriform, entorhinal, and retrosplenial cortices. TGF alpha cRNA-hybridizing cells were also localized to several thalamic nuclei and to the suprachiasmatic, dorsomedial, and ventromedial nuclei of the hypothalamus. In addition, labeled cells were present in regions of white matter including the corpus callosum, anterior commissure, internal and external capsules, optic tract, and lateral olfactory tract. Thus, both neurons and glia appear to synthesize TGF alpha in normal brain. Hybridization densities were greater in neuronal fields at 2 weeks of age compared with the adult, suggesting a role for TGF alpha in the development of several forebrain systems. Our results demonstrating the prominent and wide-spread expression of TGF alpha mRNA in forebrain, combined with the extremely low abundance of epidermal growth factor mRNA in brain, support the argument that TGF alpha is the principal endogenous ligand for the epidermal growth factor receptor in normal brain.

Odor-induced increases in c-fos mRNA expression reveal an anatomical "unit" for odor processing in olfactory bulb.

Expression of the immediate-early gene c-fos was used to evaluate the coordinate activation of olfactory bulb neurons by brief exposure to specific odors in the alert rat. In situ hybridization to c-fos mRNA was compared to regional increases in 2-deoxy-D-[14C]glucose incorporation in an adjacent section analysis. Levels of c-fos mRNA in olfactory bulb were high in rats recently removed from their home cage but were low in animals placed in a relatively odor-free chamber for 30 min. Presentation of specific odors to alert rats for as little as 5 min increased c-fos mRNA in radially distributed neuronal ensembles that spanned the lamina of the main olfactory bulb. The complementary RNA (cRNA)-labeled neuronal collectives consisted of cells in the glomerular layer that precisely defined the borders of individual glomeruli and underlying tufted, mitral, and granule cells. The activated fields were much broader in the granule cell layer than in the overlying glomerular layer and thus exhibited a flask-like, as opposed to a columnar, contour. The bulbar distribution of cRNA-labeled cell arrays differed with different odors and, in the glomerular layer, corresponded to focal regions of high 2-deoxy-D-[14C]glucose uptake. Administration of the noncompetitive N-methyl-D-aspartate receptor antagonist MK801 did not attenuate the odor induction of c-fos but, instead, increased c-fos mRNA levels throughout the bulb. We propose that the neuronal ensembles expressing increased c-fos mRNA with odor stimulation represent principal functional units of sensory processing in the main olfactory bulb of the behaving rat.

Differential expression of mRNAs for the NGF family of neurotrophic factors in the adult rat central olfactory system.

The cellular localization of mRNAs for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3), in the rat central olfactory system was evaluated with in situ hybridization of 35S-labeled cRNA probes. In the main olfactory bulb, low levels of NGF and BDNF mRNA expression were detected. NGF mRNA was restricted to the glomerular region while BDNF mRNA was predominantly localized to the granule cell layer. No cellular hybridization to NT3 cRNA was seen. The accessory olfactory bulb did not express detectable levels of mRNA for any of the three related neurotrophic factors. Areas which receive olfactory bulb afferents expressed comparatively high levels of both NGF and BDNF mRNA. Cell labeling with cRNAs for NGF and BDNF occurred throughout the cellular layers of the anterior olfactory nucleus and in layers 2 and 3 of rostral piriform cortex. BDNF mRNA expression in these areas appeared more robust than that of NGF mRNA, while NT3 mRNA was not detectable. In contrast, tenia tecta exhibited dense labeling with the cRNAs for all three neurotrophic factors. The localization of NGF mRNA to primary target neurons of the olfactory nerve in the periglomerular region of the main olfactory bulb suggests that bulb cells may influence the ingrowth and continual turnover of olfactory sensory afferents. However, as there is a strong correlation between the distribution of neurotrophic factor mRNAs within rostral olfactory structures and the distribution of centrifugal cholinergic afferents, it is more likely that bulb-derived NGF, and possibly BDNF, act on the cholinergic neurons of the basal forebrain.

Olfactory deprivation increases dopamine D2 receptor density in the rat olfactory bulb.

Unilateral olfactory deprivation during postnatal development results in significant anatomical and neurochemical changes in the deprived olfactory bulb. Perhaps the most dramatic neurochemical change is the loss of dopaminergic expression by neurons of the glomerular region. We describe here the effects of early olfactory deprivation on other elements of the bulb dopaminergic system, namely the dopamine receptors of the olfactory bulb. Rat pups had a single naris occluded on postnatal day 2 (PN2). On PN20 or PN60, animals were sacrificed and the bulbs were examined for catecholamine levels or D2 and D1 dopamine receptor binding. Receptor densities were quantified by in vitro autoradiography using the tritiated antagonists spiperone (D2) and SCH23390 (D1). Dopamine uptake sites were similarly examined using tritiated mazindol. No significant specific labeling of D1 or mazindol sites was observed in the olfactory bulbs of control or experimental animals at either age. Normal animals displayed prominent labeling of D2 sites in the glomerular and nerve layers. After 60 days of deprivation, deprived bulbs exhibited an average increase in D2 receptor density of 32%. As determined by Scatchard analysis, the mean values for Kd and Bmax were 0.134 nM and 293 fmol/mg protein in normal bulbs, and 0.136 nM and 403 fmol/mg protein in deprived bulbs. The results suggest that, as in the neostriatum, dopamine depletion in the olfactory bulb leads to an upregulation of D2 receptor sites. This change may represent an attempt by the system to adapt neurochemically to reduced dopaminergic activity and thereby maintain bulb function.

Early unilateral deprivation modifies olfactory bulb function.

Unilateral olfactory deprivation during postnatal development produces significant structural and neurochemical modifications of the olfactory bulb. In the present report, we describe the functional consequences of such deprivation. Rat pups had a single naris occluded on postnatal day 2 (PN2) to deprive them of early olfactory stimulation. On PN20-22, the occluded naris was reopened, the previously open naris was sealed, and responses of the deprived olfactory bulb to odors were assessed using both single-unit recording from mitral/tufted cells and quantitative 14C-2-deoxyglucose (2-DG) autoradiography. While the response properties of individual odor-stimulated mitral/tufted cells were not altered by early deprivation, spontaneous activity was depressed, and there was a significantly higher incidence of odor-responsive mitral/tufted cells in deprived compared to nondeprived bulbs. In addition, odor-stimulated deprived bulbs demonstrated greater uptake of 2-DG than did non-deprived bulbs. Together, these data indicate that the olfactory system demonstrates an increased responsiveness to sensory cues following early deprivation.

Modification of olfactory bulb synaptic inhibition by early unilateral olfactory deprivation.

Early unilateral olfactory deprivation produces large structural and neurochemical changes in the olfactory bulb, the first central relay for olfactory information. The functioning of deprived bulbs was examined in the present report by using paired-pulse stimulation of the lateral olfactory tract. Paired-pulse stimulation reflects interactions between mitral/tufted cells and granule cells, as well as the modulatory effects of centrifugal and intra-bulbar association fibers. Paired-pulse stimulation produced inhibition of mitral/tufted cells in control animals at PN20-PN22. This inhibition was significantly enhanced in littermates deprived of olfactory input from PN1 to PN20-PN22. Suppression of mitral/tufted cell single-unit spontaneous activity following single-pulse stimulation of the lateral olfactory tract (LOT) was similarly enhanced in deprived bulbs. These results suggest that early olfactory deprivation significantly modifies subsequent olfactory system function.