David M. Coppola

The contribution of sensory experience to the maturation of orientation selectivity in ferret visual cortex

Sensory experience begins when neural circuits in the cerebral cortex are still immature; however, the contribution of experience to cortical maturation remains unclear. In the visual cortex, the selectivity of neurons for oriented stimuli at the time of eye opening is poor and increases dramatically after the onset of visual experience. Here we investigate whether visual experience has a significant role in the maturation of orientation selectivity and underlying cortical circuits using two forms of deprivation: dark rearing, which completely eliminates experience, and binocular lid suture, which alters the pattern of sensory driven activity. Orientation maps were present in dark-reared ferrets, but fully mature levels of tuning were never attained. In contrast, only rudimentary levels of orientation selectivity were observed in lid-sutured ferrets. Despite these differences, horizontal connections in both groups were less extensive and less clustered than normal, suggesting that long-range cortical processing is not essential for the expression of orientation selectivity, but may be needed for the full maturation of tuning. Thus, experience is beneficial or highly detrimental to cortical maturation, depending on the pattern of sensory driven activity.

Universality in the Evolution of Orientation Columns in the Visual Cortex

Orientation Columns In the brains visual cortex, certain neurons respond to vertical lines and others to horizontal lines, with a range in between. Such orientation of neurons tends to be organized in columns reflecting similar responses, and the columns are organized in pinwheels representing the range of responses. Kaschube et al. (p. 1113, published online 4 November; see the Perspective by Miller) looked at the organization of orientation columns in diverse placental mammals and discovered a similarity of organizational principles. Analysis of evolutionarily divergent species highlights constraint on brain structure imposed by self-organizing neural networks. The brain’s visual cortex processes information concerning form, pattern, and motion within functional maps that reflect the layout of neuronal circuits. We analyzed functional maps of orientation preference in the ferret, tree shrew, and galago—three species separated since the basal radiation of placental mammals more than 65 million years ago—and found a common organizing principle. A symmetry-based class of models for the self-organization of cortical networks predicts all essential features of the layout of these neuronal circuits, but only if suppressive long-range interactions dominate development. We show mathematically that orientation-selective long-range connectivity can mediate the required interactions. Our results suggest that self-organization has canalized the evolution of the neuronal circuitry underlying orientation preference maps into a single common design.

Naris occlusion alters olfactory marker protein immunoreactivity in olfactory epithelium.

Though its function remains obscure, olfactory marker protein (OMP) has been implicated in olfactory transduction and the enhancement of neurogenesis within olfactory epithelium. Here we show, using Western blot analysis and immunocytochemistry, that unilateral naris occlusion (UNO) on postnatal day 1 alters OMP immunoreactivity (IR) differentially on the occluded and non-occluded sides of the nasal cavity in 18, 24 and 70-day-old mice. Compared to untreated animals, UNO-treated animals had a decrease in OMP-IR in olfactory receptor neurons on the non-occluded side and an increase in OMP-IR in olfactory receptor neurons on the occluded side of the nasal cavity. These results suggest that OMP concentration is up- or down-regulated depending on the amount of odor stimulation olfactory receptor neurons receive. It is proposed that this apparent change in protein concentration may be part of a more general compensatory response by olfactory neurons to levels of odor in the environment.

Naris occlusion alters the electro-olfactogram: Evidence for compensatory plasticity in the olfactory system

Unilateral naris occlusion (NO) has been widely used as a method of olfactory deprivation to study the role of stimulus-driven activity in olfactory development [P.C. Brunjes, Unilateral naris closure and olfactory system development, Brain Res. Rev. 19 (1994) 146-160]. Recent immunochemical studies of the olfactory epithelium (OE) following NO provide evidence for a previously unknown compensatory response to deprivation [D.M. Coppola, A. Waguespack, M. Reems, M.L. Butman, J. Cherry, Naris occlusion alters transductory protein immunoreactivity in olfactory epithelium, Histol. Histopathol. 21 (2006) 487-501; A. Waguespack, M. Reems, M.L. Butman, J. Cherry, D.M. Coppola, Olfactory receptor neurons have enhanced olfactory marker protein immunoreactivity in the nasal cavity ipsilateral to naris occlusion, Brain Res. 1044 (2005) 1-7]. To further investigate this phenomenon we measured electro-olfactograms (EOG) from the open and occluded OE of adult mice that had undergone NO as newborns. EOG waveforms from the open side OE of NO mice were indistinguishable from those obtained from untreated animals. However, amplitudes of EOGs from the occluded OE of NO mice were greater, on average, than those recorded at matched locations from the open side. This result was consistent across turbinates, odors, and all but the highest odor concentration. In addition, EOGs recorded from the occluded OE had significantly slower onset and recovery kinetics. Responses in a double-pulse protocol confirmed that the kinetics of the cellular or population processes that underlie the EOG are slowed by NO. These results provide the most direct support, to date, for compensatory plasticity in the olfactory system.

Visual experience promotes the isotropic representation of orientation preference

Within the visual cortex of several mammalian species, more circuitry is devoted to the representation of vertical and horizontal orientations than oblique orientations. The sensitivity of this representation of orientation preference to visual experience during cortical maturation and the overabundance of cardinal contours in the environment suggest that vision promotes the development of this cortical anisotropy. We tested this idea by measuring the distribution of cortical orientation preference and the degree of orientation selectivity in developing normal and dark-reared ferrets using intrinsic signal optical imaging. The area of the angle map of orientation preference representing cardinal and oblique orientations was determined; in addition, orientation selectivity indices were computed separately for cardinal and oblique difference images. In normal juvenile animals, we confirm a small, but statistically significant overrepresentation of near horizontal orientations in the cortical angle map. However, the degree of anisotropy did not increase in the weeks that followed eye opening when orientation selectivity matured; rather, it decreased. In dark-reared ferrets, an even greater cortical anisotropy emerged, but angle maps in these animals developed an apparently anomalous overrepresentation of near vertical orientations. Thus, the overrepresentation of cardinal orientations in the visual cortex does not require experience with an anisotropic visual environment; indeed, cortical anisotropy can develop in the complete absence of vision. These observations suggest that the role of visual experience in cortical maturation is to promote the isotropic representation of orientation preference.

The effects of unilateral naris occlusion on gene expression profiles in mouse olfactory mucosa.

Unilateral naris occlusion has been the method of choice for effecting stimulus deprivation in studies of olfactory plasticity. Early experiments emphasized the deleterious effects of this technique on the developing olfactory system while more recent studies have pointed to several apparently “compensatory” responses. However, the evidence for deprivation-induced compensatory processes in olfaction remains fragmentary. High-throughput methods such as microarray analysis can help fill the deficits in our understanding of naris occlusion as a mode of stimulus deprivation. Here we report for young adult mice the effects of early postnatal naris occlusion on the olfactory mucosal transcriptome using microarray analysis with RT–PCR confirmation. The transcripts of key genes involved in olfactory reception, transduction, and transmission were up-regulated in deprived-side olfactory mucosa, with opposite effects in non-deprived-side mucosa, compared to controls. Results support the hypothesis that odor environment triggers a previously unknown homeostatic control mechanism in olfactory receptor neurons designed to maximize information transfer.

How does long-term odor deprivation affect the olfactory capacity of adult mice?

BackgroundUnilateral naris occlusion (UNO) has been the most common method of effecting stimulus deprivation in studies of olfactory plasticity. However, despite the large corpus on the effects of this manipulation, dating back to the 19th century, little is known about its behavioral sequela. Here we report the results of standard olfactory habituation and discrimination studies on adult mice that had undergone perinatal UNO followed by adult contralateral olfactory bulbectomy (bulb-x).MethodsThe olfactory performance of UNO mice was compared to matched controls that had unilateral bulb-x but open nares. Both habituation and discrimination (operant) experiments employed a protocol in which after successful dishabituation or discrimination to dilute individual odors (A = 0.01% isoamyl acetate; B = 0.01% ethyl butyrate; each v/v in mineral oil), mice were challenged with a single odor versus a mixture comparison (A vs. A + B). In a series of tests the volume portion of Odor B in the mixture was systematically decreased until dishabituation or discrimination thresholds were reached.ResultsFor the habituation experiment, UNOs (n = 10) and controls (n = 9) dishabituated to a 10% mixture of Odor B in Odor A after being habituated to A alone, while both groups failed to show differential responding to a 2% mixture of B in A. However, the UNO groups increased investigation durations for the 2% mixture approached significance (p < 0.06). A replication of this study (7 controls & 8 UNOs) confirmed that controls did not differentiate Odor A and a 2% mixture of B in A but UNOs did not (p < 0.05). For the discrimination experiment, 4 UNOs and 4 controls were shaped to dig in one of two containers of sand that contained the S+ odor (Odor B) to obtain sugar pellet rewards. As in the habituation experiment, UNOs displayed greater olfactory capacity than controls on this task. Controls and UNOs had an average mixture discrimination threshold of 1.6% (± 0.4) and 0.22% (± 0.102) respectively, a difference that was statistically significant (p < 0.02).ConclusionsAdult mice relying on an olfactory system deprived of odor by naris occlusion from near the time of birth display enhanced olfactory capacity compared to control mice. This counterintuitive result suggests that UNO is neither an absolute method of deprivation nor does it diminish olfactory capabilities. Enhanced olfactory capacity, as observed in the current study, that is a consequence of deprivation, is consistent with recent molecular and physiological evidence that stimulus deprivation triggers compensatory processes throughout the olfactory system.

The effects of naris occlusion on mouse nasal turbinate development

Unilateral naris occlusion, a standard method for causing odor deprivation, also alters airflow on both sides of the nasal cavity. We reasoned that manipulating airflow by occlusion could affect nasal turbinate development given the ubiquitous role of environmental stimuli in ontogenesis. To test this hypothesis, newborn mice received unilateral occlusion or sham surgery and were allowed to reach adulthood. Morphological measurements were then made of paraffin sections of the whole nasal cavity. Occlusion significantly affected the size, shape and position of turbinates. In particular, the nasoturbinate, the focus of our quantitative analysis, had a more delicate appearance on the occluded side relative to the open side. Occlusion also caused an increase in the width of the dorsal meatus within the non-occluded and occluded nasal fossae, compared with controls, and the position of most turbinates was altered. These results suggest that a mechanical stimulus from respiratory airflow is necessary for the normal morphological development of turbinates. To explore this idea, we estimated the mechanical forces on turbinates caused by airflow during normal respiration that would be absent as a result of occlusion. Magnetic resonance imaging scans were used to construct a three-dimensional model of the mouse nasal cavity that provided the input for a computational fluid dynamics simulation of nasal airflow. The simulation revealed maximum shear stress values for the walls of turbinates in the 1 Pa range, a magnitude that causes remodeling in other biological tissues. These observations raise the intriguing possibility that nasal turbinates develop partly under the control of respiratory mechanical forces.

The Role of the Main and Accessory Olfactory Systems in Prenatal Olfaction

Olfaction, an “early” sensory system both phylogenetically and ontogenetically, is required for survival in the newborn mammal. For example, odor cues orient neonates to their mother, her nipples and the nest; neonatal house mice whose olfactory bulbs are lesioned subsequently undergo fatal malnutrition (Coppola et al., 1994). Altricial rodents, like the mouse and rat, are not only born deaf and blind but are denied vision and hearing for some time after birth.

Random Wiring, Ganglion Cell Mosaics, and the Functional Architecture of the Visual Cortex

The architecture of iso-orientation domains in the primary visual cortex (V1) of placental carnivores and primates apparently follows species invariant quantitative laws. Dynamical optimization models assuming that neurons coordinate their stimulus preferences throughout cortical circuits linking millions of cells specifically predict these invariants. This might indicate that V1’s intrinsic connectome and its functional architecture adhere to a single optimization principle with high precision and robustness. To validate this hypothesis, it is critical to closely examine the quantitative predictions of alternative candidate theories. Random feedforward wiring within the retino-cortical pathway represents a conceptually appealing alternative to dynamical circuit optimization because random dimension-expanding projections are believed to generically exhibit computationally favorable properties for stimulus representations. Here, we ask whether the quantitative invariants of V1 architecture can be explained as a generic emergent property of random wiring. We generalize and examine the stochastic wiring model proposed by Ringach and coworkers, in which iso-orientation domains in the visual cortex arise through random feedforward connections between semi-regular mosaics of retinal ganglion cells (RGCs) and visual cortical neurons. We derive closed-form expressions for cortical receptive fields and domain layouts predicted by the model for perfectly hexagonal RGC mosaics. Including spatial disorder in the RGC positions considerably changes the domain layout properties as a function of disorder parameters such as position scatter and its correlations across the retina. However, independent of parameter choice, we find that the model predictions substantially deviate from the layout laws of iso-orientation domains observed experimentally. Considering random wiring with the currently most realistic model of RGC mosaic layouts, a pairwise interacting point process, the predicted layouts remain distinct from experimental observations and resemble Gaussian random fields. We conclude that V1 layout invariants are specific quantitative signatures of visual cortical optimization, which cannot be explained by generic random feedforward-wiring models.