Kenneth C. Catania

Development of partner preferences in female prairie voles (Microtus ochrogaster): The role of social and sexual experience.

Prairie voles (Microtus ochrogaster) exhibit a monogamous mating system characterized by long-term pair bonds between mates. The purpose of this study was to examine the effect of cohabitation time and sexual experience on the development of pair bond formation in female prairie voles. Females that were allowed to cohabit for 24 hr or more, with or without mating, exhibited a strong social preference for a familiar partner versus a strange male. Females that cohabited and mated for 6 hr showed strong preferences for a familiar partner, while cohabitation for less than 24 hr, without mating, did not result in preferences for the familiar male. These results indicate that mating was not essential for partner preference formation; however, preferences developed more rapidly when mating occurred.

Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat

The naked mole-rat is the longest living rodent with a maximum lifespan exceeding 28 years. In addition to its longevity, naked mole-rats have an extraordinary resistance to cancer as tumors have never been observed in these rodents. Furthermore, we show that a combination of activated Ras and SV40 LT fails to induce robust anchorage-independent growth in naked mole-rat cells, while it readily transforms mouse fibroblasts. The mechanisms responsible for the cancer resistance of naked mole-rats were unknown. Here we show that naked mole-rat fibroblasts display hypersensitivity to contact inhibition, a phenomenon we termed “early contact inhibition.” Contact inhibition is a key anticancer mechanism that arrests cell division when cells reach a high density. In cell culture, naked mole-rat fibroblasts arrest at a much lower density than those from a mouse. We demonstrate that early contact inhibition requires the activity of p53 and pRb tumor suppressor pathways. Inactivation of both p53 and pRb attenuates early contact inhibition. Contact inhibition in human and mouse is triggered by the induction of p27Kip1. In contrast, early contact inhibition in naked mole-rat is associated with the induction of p16Ink4a. Furthermore, we show that the roles of p16Ink4a and p27Kip1 in the control of contact inhibition became temporally separated in this species: the early contact inhibition is controlled by p16Ink4a, and regular contact inhibition is controlled by p27Kip1. We propose that the additional layer of protection conferred by two-tiered contact inhibition contributes to the remarkable tumor resistance of the naked mole-rat.

Telomerase activity coevolves with body mass not lifespan.

In multicellular organisms, telomerase is required to maintain telomere length in the germline but is dispensable in the soma. Mice, for example, express telomerase in somatic and germline tissues, while humans express telomerase almost exclusively in the germline. As a result, when telomeres of human somatic cells reach a critical length the cells enter irreversible growth arrest called replicative senescence. Replicative senescence is believed to be an anticancer mechanism that limits cell proliferation. The difference between mice and humans led to the hypothesis that repression of telomerase in somatic cells has evolved as a tumor‐suppressor adaptation in large, long‐lived organisms. We tested whether regulation of telomerase activity coevolves with lifespan and body mass using comparative analysis of 15 rodent species with highly diverse lifespans and body masses. Here we show that telomerase activity does not coevolve with lifespan but instead coevolves with body mass: larger rodents repress telomerase activity in somatic cells. These results suggest that large body mass presents a greater risk of cancer than long lifespan, and large animals evolve repression of telomerase activity to mitigate that risk.

Anatomic correlates of the face and oral cavity representations in the somatosensory cortical area 3b of monkeys.

We determined the somatotopy of the face and the oral cavity representation in cortical area 3b of New World owl monkeys and squirrel monkeys. Area 3b is apparent as a densely myelinated strip in brain sections cut parallel to the surface of flattened cortex. A narrow myelin‐light septum that we have termed the “hand‐face septum” separates the hand representation from the more lateral face and mouth representation. The face and oral cavity representation is further divided into a series of myelin‐dense ovals. We show that three ovals adjacent to the hand representation correspond to the upper face, upper lip, and chin plus lower lip, whereas three or four more rostral ovals successively represent the contralateral teeth, tongue, and the ipsilateral teeth and tongue. Strips of cortex lateral and medial to the area 3b ovals, possibly corresponding to area 1 and area 3a, respectively, have similar somatotopic sequences. Although previous results suggest the existence of great variability within and across primate species, we conclude that the representations of the face and mouth are highly similar across individuals of the same species, and there are extensive overall similarities across these two species of New World monkeys. J. Comp. Neurol. 429:455–468, 2001.

Somatosensory fovea in the star‐nosed mole: Behavioral use of the star in relation to innervation patterns and cortical representation

Eleven fleshy appendages, or rays, surround each of the nostrils of the star‐nosed mole. Each ray is covered with tactile sensory organs, and each ray is represented in the cortex by a stripe of tissue visible in brain sections processed for cytochrome oxidase. Here we report that the 11th, ventral ray is the behavioral focus of the nose. This ray is preferentially used to explore prey items by touch, in a behavior pattern similar to the use of a fovea in the visual system. After prey is first contacted with any nasal ray, subsequent touches are centered on the 11th ray. Although the 11th ray is small and has relatively few sensory organs on its surface, it has the largest cortical representation, greatest area of cortex per sensory organ, and the highest innervation density per sensory organ. In addition, the average area of cortex per primary afferent is highest for this ray. We refer to the differential magnification of first‐order afferents in the cortical representation as “afferent magnification.” The patterns of both cortical magnification (cortical area per sensory organ) and afferent magnification (cortical area per afferent) of the rays correlated highly with the distribution of touches across the nose scored from videotaped behavior. A simple model of star‐nosed mole behavior predicts the distribution of touches across the rays and also correlates highly with both the actual pattern of behavior and the patterns of cortical magnification observed. J. Comp. Neurol. 387:215–233, 1997.

Organization of somatosensory cortex in the laboratory rat (Rattus norvegicus): Evidence for two lateral areas joined at the representation of the teeth

Lateral somatosensory areas have not been explored in detail in rats, and theories on the organization of this region are based largely on anatomical tracing experiments. We investigated the topography of this region by using microelectrode recordings, which were related to flattened cortical sections processed for cytochrome oxidase (CO). Two lateral somatosensory areas were identified, each containing a complete representation of the body. A larger, more medial representation formed a mirror image of S1 along the rostrocaudal axis of the head region corresponding to the previously identified secondary somatosensory area (S2). A smaller, more lateral representation formed a mirror image of S2 along the rostrocaudal axis of the forelimb and hindlimb regions and likely corresponds to the parietal ventral area (PV) identified in other mammals. We also investigated the representation of the dentition and identified regions of cortex responsive to tooth stimulation. The lower incisor representation was rostral to the lower lip region of S1, and the upper incisor representation was lateral to the buccal pad region of S1. The upper and lower incisors flanked the tongue representation. An additional large region of far lateral cortex responded to both incisors. Finally, five CO‐dense modules were consistently identified rostral and lateral to the S1 face representation, which we refer to as OM1, OM2, OM3, FM, and HM. These modules closely correspond to the physiologically identified areas representing the lower incisor (OM1) and tongue (OM2) regions of S1 and the mixed tooth (OM3), forelimb (FM1), and hindlimb (HM) representations of S2 and PV. J. Comp. Neurol. 467:105–118, 2003.

Somatosensory cortex dominated by the representation of teeth in the naked mole-rat brain

We investigated naked mole-rat somatosensory cortex to determine how brain areas are modified in mammals with unusual and extreme sensory specializations. Naked mole-rats (Heterocephalus glaber) have numerous anatomical specializations for a subterranean existence, including rows of sensory hairs along the body and tail, reduced eyes, and ears sensitive to low frequencies. However, chief among their adaptations are behaviorally important, enlarged incisors permanently exterior to the oral cavity that are used for digging, object manipulation, social interactions, and feeding. Here we report an extraordinary brain organization where nearly one-third (31%) of primary somatosensory cortex is devoted to the representations of the upper and lower incisors. In addition, somatosensory cortex is greatly enlarged (as a proportion of total neocortical area) compared with closely related laboratory rats. Finally, somatosensory cortex in naked mole-rats encompasses virtually all of the neocortex normally devoted to vision. These findings indicate that major cortical remodeling has occurred in naked mole-rats, paralleling the anatomical and behavioral specializations related to fossorial life.

Cortical organization in shrews: Evidence from five species

Cortical organization was examined in five shrew species. In three species, Blarina brevicauda, Cryptotis parva, and Sorex palustris, microelectrode recordings were made in cortex to determine the organization of sensory areas. Cortical recordings were then related to flattened sections of cortex processed for cytochrome oxidase or myelin to reveal architectural borders. An additional two species (Sorex cinereus and Sorex longirostris) with visible cortical subdivisions based on histology alone were analyzed without electrophysiological mapping. A single basic plan of cortical organization was found in shrews, consisting of a few clearly defined sensory areas located caudally in cortex. Two somatosensory areas contained complete representations of the contralateral body, corresponding to primary somatosensory cortex (S1) and secondary somatosensory cortex (S2). A small primary visual cortex (V1) was located closely adjacent to S1, whereas auditory cortex (A1) was located in extreme caudolateral cortex, partially encircled by S2. Areas did not overlap and had sharp, histochemically apparent and electrophysiologically defined borders. The adjacency of these areas suggests a complete absence of intervening higher level or association areas. Based on a previous study of corticospinal connections, a presumptive primary motor cortex (M1) was identified directly rostral to S1. Apparently, in shrews, the solution to having extremely little neocortex is to have only a few small cortical subdivisions. However, the small areas remain discrete, well organized, and functional. This cortical organization in shrews is likely a derived condition, because a wide range of extant mammals have a greater number of cortical subdivisions. J. Comp. Neurol. 410:55–72, 1999.

Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan

Large, long‐lived species experience more lifetime cell divisions and hence a greater risk of spontaneous tumor formation than smaller, short‐lived species. Large, long‐lived species are thus expected to evolve more elaborate tumor suppressor systems. In previous work, we showed that telomerase activity coevolves with body mass, but not lifespan, in rodents: telomerase activity is repressed in the somatic tissues of large rodent species but remains active in small ones. Without telomerase activity, the telomeres of replicating cells become progressively shorter until, at some critical length, cells stop dividing. Our findings therefore suggested that repression of telomerase activity mitigates the increased risk of cancer in larger‐bodied species but not necessarily longer‐lived ones. These findings imply that other tumor suppressor mechanisms must mitigate increased cancer risk in long‐lived species. Here, we examined the proliferation of fibroblasts from 15 rodent species with diverse body sizes and lifespans. We show that, consistent with repressed telomerase activity, fibroblasts from large rodents undergo replicative senescence accompanied by telomere shortening and overexpression of p16Ink4a and p21Cip1/Waf1 cycline‐dependent kinase inhibitors. Interestingly, small rodents with different lifespans show a striking difference: cells from small shorter‐lived species display continuous rapid proliferation, whereas cells from small long‐lived species display continuous slow proliferation. We hypothesize that cells of small long‐lived rodents, lacking replicative senescence, have evolved alternative tumor‐suppressor mechanisms that prevent inappropriate cell division in vivo and slow cell growth in vitro. Thus, large‐bodied species and small but long‐lived species have evolved distinct tumor suppressor mechanisms.

Cellular scaling rules of insectivore brains

Insectivores represent extremes in mammalian body size and brain size, retaining various “primitive” morphological characteristics, and some species of Insectivora are thought to share similarities with small-bodied ancestral eutherians. This raises the possibility that insectivore brains differ from other taxa, including rodents and primates, in cellular scaling properties. Here we examine the cellular scaling rules for insectivore brains and demonstrate that insectivore scaling rules overlap somewhat with those for rodents and primates such that the insectivore cortex shares scaling rules with rodents (increasing faster in size than in numbers of neurons), but the insectivore cerebellum shares scaling rules with primates (increasing isometrically). Brain structures pooled as “remaining areas” appear to scale similarly across all three mammalian orders with respect to numbers of neurons, and the numbers of non-neurons appear to scale similarly across all brain structures for all three orders. Therefore, common scaling rules exist, to different extents, between insectivore, rodent, and primate brain regions, and it is hypothesized that insectivores represent the common aspects of each order. The olfactory bulbs of insectivores, however, offer a noteworthy exception in that neuronal density increases linearly with increasing structure mass. This implies that the average neuronal cell size decreases with increasing olfactory bulb mass in order to accommodate greater neuronal density, and represents the first documentation of a brain structure gaining neurons at a greater rate than mass. This might allow insectivore brains to concentrate more neurons within the olfactory bulbs without a prohibitively large and metabolically costly increase in structure mass.