Multiple Timescales Account for Adaptive Responses across Sensory Cortices.

Sensory systems encounter remarkably diverse stimuli in the external environment. Natural stimuli exhibit timescales and amplitudes of variation that span a wide range. Mechanisms of adaptation, a ubiquitous feature of sensory systems, allow for the accommodation of this range of scales. Are there common rules of adaptation across different sensory modalities? We measured the membrane potential responses of individual neurons in the visual, somatosensory, and auditory cortices of male and female mice to discrete, punctate stimuli delivered at a wide range of fixed and nonfixed frequencies. We find that the adaptive profile of the response is largely preserved across these three areas, exhibiting attenuation and responses to the cessation of stimulation, which are signatures of response to changes in stimulus statistics. We demonstrate that these adaptive responses can emerge from a simple model based on the integration of fixed filters operating over multiple time scales.SIGNIFICANCE STATEMENT Our recent sensations affect our current expectations and perceptions of the environment. Neural correlates of this process exist throughout the brain and are loosely termed adaptation. Adaptive processes have been described across sensory cortices, but direct comparisons of these processes have not been possible because paradigms have been tailored specifically for each modality. We developed a common stimulus set that was used to characterize adaptation in somatosensory, visual, and auditory cortex. We describe here the similarities and differences in adaptation across these cortical areas and demonstrate that adaptive responses may emerge from a set of static filters that operate over a broad range of timescales.

A retinal source of spatial contrast gain control.

Sensory cortex is able to encode a broad range of stimulus features despite a great variation in signal strength. In cat primary visual cortex (V1), for example, neurons are able to extract stimulus features like orientation or spatial configuration over a wide range of stimulus contrasts. The contrast-invariant spatial tuning found in V1 neuron responses has been modeled as a gain control mechanism, but at which stage of the visual pathway it emerges has remained unclear. Here we describe our findings that contrast-invariant spatial tuning occurs not only in the responses of lateral geniculate nucleus (LGN) relay cells but also in their afferent retinal input. Our evidence suggests that a similar contrast-invariant mechanism is found throughout the stages of the early visual pathway, and that the contrast-invariant spatial selectivity is evident in both retinal ganglion cell and LGN cell responses.

Low-dimensional encoding of decisions in parietal cortex reflects long-term training history.

Neurons in parietal cortex exhibit task-related activity during decision-making tasks. However, it remains unclear how long-term training to perform different tasks over months or even years shapes neural computations and representations. We examine lateral intraparietal area (LIP) responses during a visual motion delayed-match-to-category task. We consider two pairs of male macaque monkeys with different training histories: one trained only on the categorization task, and another first trained to perform fine motion-direction discrimination (i.e., pretrained). We introduce a novel analytical approach-generalized multilinear models-to quantify low-dimensional, task-relevant components in population activity. During the categorization task, we found stronger cosine-like motion-direction tuning in the pretrained monkeys than in the category-only monkeys, and that the pretrained monkeys' performance depended more heavily on fine discrimination between sample and test stimuli. These results suggest that sensory representations in LIP depend on the sequence of tasks that the animals have learned, underscoring the importance of considering training history in studies with complex behavioral tasks.

Improved clinicopathologic assessments of acute liver damage due to trauma in Indian ring-necked parakeets (Psittacula krameri manillensis).

Increased activities of certain biochemical enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase [LDH], alkaline phosphatase [ALP]) have been associated with blunt liver injury in many species. To evaluate changes in plasma hepatic biochemical parameters in acute avian liver disease caused by trauma and to compare biochemical changes with histologic lesions in hepatic parenchyma, 30 healthy fasted Indian ring-necked parakeets (Psittacula krameri manillensis) were divided into 2 groups, and traumatic liver injury was caused by endoscopic liver biopsy (group 1) or by liver biopsy and crushing injury to the hepatic parenchyma with endoscopic forceps (group 2) in anesthetized birds. Blood samples were collected at baseline and at 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120 hours in alternate groups to compare analyte values after injury with those at baseline. Results showed consistently decreased plasma ALP activity (excluding 1 time point) throughout the study, which was thought to be associated with isoflurane administration. Plasma glutamate dehydrogenase activity initially increased but rapidly declined thereafter and was attributed to acute focal hepatocellular injury. In both groups, increases in plasma AST, ALT, and LDH activities was most likely caused by muscle injury because creatine kinase activity was concurrently increased. Compared with baseline values, bile acid concentration and y-glutamyl transferase activity were not affected by liver biopsy or crush injury. Plasma sorbitol dehydrogenase activity was the most specific indicator of liver injury in both groups. Histologic changes correlated poorly with biochemical results, possibly because the small area of hepatic parenchyma that was damaged did not affect enzyme values substantially.

Dopamine neurons evaluate natural fluctuations in performance quality.

Many motor skills are learned by comparing ongoing behavior to internal performance benchmarks. Dopamine neurons encode performance error in behavioral paradigms where error is externally induced, but it remains unknown whether dopamine also signals the quality of natural performance fluctuations. Here, we record dopamine neurons in singing birds and examine how spontaneous dopamine spiking activity correlates with natural fluctuations in ongoing song. Antidromically identified basal ganglia-projecting dopamine neurons correlate with recent, and not future, song variations, consistent with a role in evaluation, not production. Furthermore, maximal dopamine spiking occurs at a single vocal target, consistent with either actively maintaining the existing song or shifting the song to a nearby form. These data show that spontaneous dopamine spiking can evaluate natural behavioral fluctuations unperturbed by experimental events such as cues or rewards.

Proceedings of the 2009 National Toxicology Program Satellite Symposium.

The National Toxicology Program (NTP) Satellite Symposium is a one-day meeting that is held in conjunction with the annual Society of Toxicologic Pathology (STP) meeting. The topic of the 2009 Symposium was "Tumor Pathology and INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Nomenclature." The goal of this article is to provide summaries of each speaker's presentation, including the diagnostic or nomenclature issues that were presented, along with a few select images that were used for voting. The results of the voting process and interesting points of discussion that were raised during the presentation are also provided. A supplemental file with voting choices and voting results for each case presented at the symposium is available at http://tpx.sagepub.com/supplemental.

Gingival osteogenic melanoma in two dogs.

Osteogenic melanoma is a rare variant of metaplastic malignant melanoma in human medicine and appears to be a similarly rare variant in dogs. Two dogs with oral malignant melanoma with neoplastic bone formation are reported in this study. Both tumors were characterized by malignant melanocytes that transitioned into neoplastic bone at the deep margins of the neoplasm. Immunohistochemical analysis revealed S100- and Melan-A-positive neoplastic cells adjacent to, and occasionally embedded within, an osteoid and chondroblastic matrix. Scattered clusters of neoplastic cells were also positive for osteocalcin. The findings indicate that in dogs, as in humans, neoplastic melanocytes have metaplastic potential and can be osteogenic.

Capturing Multiple Timescales of Adaptation to Second-Order Statistics With Generalized Linear Models: Gain Scaling and Fractional Differentiation.

Single neurons can dynamically change the gain of their spiking responses to take into account shifts in stimulus variance. Moreover, gain adaptation can occur across multiple timescales. Here, we examine the ability of a simple statistical model of spike trains, the generalized linear model (GLM), to account for these adaptive effects. The GLM describes spiking as a Poisson process whose rate depends on a linear combination of the stimulus and recent spike history. The GLM successfully replicates gain scaling observed in Hodgkin-Huxley simulations of cortical neurons that occurs when the ratio of spike-generating potassium and sodium conductances approaches one. Gain scaling in the GLM depends on the length and shape of the spike history filter. Additionally, the GLM captures adaptation that occurs over multiple timescales as a fractional derivative of the stimulus envelope, which has been observed in neurons that include long timescale afterhyperpolarization conductances. Fractional differentiation in GLMs requires long spike history that span several seconds. Together, these results demonstrate that the GLM provides a tractable statistical approach for examining single-neuron adaptive computations in response to changes in stimulus variance.

Genetic variability of Cytauxzoon felis from 88 infected domestic cats in Arkansas and Georgia.

Although cytauxzoonosis has historically been nearly 100% fatal in domestic cats, increasing number of reports of infected cats that demonstrate less-severe disease suggest the existence of different strains of Cytauxzoon felis. To test this hypothesis, the genetic variability of C. felis was examined in blood samples from naturally infected domestic cats from Arkansas and Georgia by using the first and second ribosomal internal transcribed spacer regions (ITS1, ITS2) as markers to assess genotypic variability. In addition, the clinical outcome of infection (survival vs. fatal disease) was analyzed. Within the C. felis ITS1 region, there were a total of 8 single nucleotide polymorphisms (SNP) and a single nucleotide insertion. Within the ITS2 region, there were a total of 4 SNPs and a single 40 base pair insertion. When taken together, the ITS1 and ITS2 sequence data defined a total of 11 different sequences and 3 unique genotypes. One unique ITS1-ITS2 genotype was detected in samples submitted exclusively from Arkansas, and a second unique genotype was submitted exclusively from Georgia. There was a significant association between infection with C. felis that contained particular ITS genotypes and survival of the infected domestic cat. The identification of unique C. felis genotypes obtained from different geographic areas and the association of particular ITS genotypes with the outcome of infection suggest the existence of parasite strains that may vary in pathogenicity to the domestic cat and offer an explanation for the survival of some infected cats in more recent case studies.

Genetic variability of archived Cytauxzoon felis histologic specimens from domestic cats in Georgia, 1995-2007.

Cytauxzoon felis infection in domestic cats has historically been nearly 100% fatal. However, increasing reports of domestic cats that survive cytauxzoonosis and reports of asymptomatic cats with C. felis infections suggest the existence of different parasite strains that vary in pathogenicity. The objective of the current study was to obtain epidemiologic information about cytauxzoonosis through genotypic characterization of archived histologic specimens from domestic cats with C. felis infections that were diagnosed in Georgia between 1995 and 2007. Such retrospective data on genetic variability will provide an historic context for current studies of C. felis genotype frequencies. Cytauxzoon felis DNA was obtained from formalin-fixed, paraffin-embedded tissues from infected cats diagnosed with cytauxzoonosis at necropsy. Genetic characterization of C. felis was performed using sequence analysis of the polymerase chain reaction-amplified ribosomal internal transcribed spacer regions 1 and 2 (ITS1, ITS2). Eleven different combined ITS1 and ITS2 sequences were identified, the majority of which were identical to those previously reported in fatally infected cats from Georgia. The findings of the current study document the existence of genetically distinct C. felis populations in historical samples and, together with data from contemporary samples, demonstrate a diverse population structure for C. felis.

Systemic adenovirus infection in Sulawesi tortoises (Indotestudo forsteni) caused by a novel siadenovirus.

A novel siadenovirus was identified in the Sulawesi tortoise (Indotestudo forsteni). A group of 105 Sulawesi tortoises was obtained by the Turtle Survival Alliance. Many of the tortoises were in poor health. Clinical signs included anorexia, lethargy, mucosal ulcerations and palatine erosions of the oral cavity, nasal and ocular discharge, and diarrhea. Initial diagnostic tests included fecal testing for parasites, complete blood count and plasma biochemical analysis, mycoplasma serology, and polymerase chain reaction (PCR) testing for intranuclear coccidia and chelonian herpesvirus. Treatment included administration of antibiotics, antiparasitic medications, parenteral fluids, and nutritional support. Tissue samples from animals that died were submitted for histopathologic evaluation. Histopathologic examination revealed systemic inflammation and necrosis associated with intranuclear inclusions consistent with a systemic viral infection in 35 tortoises out of 50 examined. Fecal testing results and histopathologic findings revealed intestinal and hepatic amoebiasis and nematodiasis in 31 animals. Two of 5 tortoises tested by PCR were positive for Chlamydophila sp. Aeromonas hydrophila and Escherichia coli were cultured from multiple organs of 2 animals. The mycoplasma serology and PCR results for intranuclear coccidia and chelonian herpesvirus were negative. Polymerase chain reaction testing of tissues, plasma, and choanal/cloacal samples from 41 out of 42 tortoises tested were positive for an adenovirus, which was characterized by sequence analysis and molecular phylogenetic inference as a novel adenovirus of the genus Siadenovirus. The present report details the clinical and anatomic pathologic findings associated with systemic infection of Sulawesi tortoises by this novel Siadenovirus, which extends the known reptilian adenoviruses to the chelonians and extends the known genera of reptilian Adenoviridae beyond Atadenovirus to include the genus Siadenovirus.

Atoxoplasmosis in canary fledglings: severe lymphocytic enteritis with preferential parasitism of B lymphocytes.

All fledgling canaries (Serinum canarius) in a small private aviary died from atoxoplasmosis during a single breeding season. The birds were clinically normal when removed from their parents at 2 mo of age, but by 3 mo of age all had died following an illness characterized by progressive lethargy, anorexia, and debilitation. Cachexia, splenomegaly, and pale foci in the liver were evident at necropsy. Microscopically, there was striking infiltration of the intestinal lamina propria by mononuclear cells that contained intracytoplasmic protozoa. Protozoa were also observed in mononuclear cells in splenic and hepatic sinusoids and in vascular or perivascular spaces of other organs, but were much less numerous. Ultrastructural features of infected enteric mononuclear cells were suggestive of lymphocytes, and the majority of parasitized cells in paraffin sections of intestine were positive for CD-79 antigen, consistent with B lymphocytes. CD-3 staining was minimal, suggesting little or no T-cell infection. The following year, after egg-laying was completed, adults were treated with sulfadimethoxine, and no further fledgling losses occurred.

Investigation of shell disease in map turtles (Graptemys spp.).

Nineteen map turtles (Graptemys spp.) maintained under natural conditions were investigated because of chronic shell abnormalities. Animals were evaluated using a novel shell scoring system that divided the 54 scutes into six regions, with each region scored for lesion extent and severity, and summated to produce a total shell disease score (TSDS). Complete blood counts and various biochemistry analytes (total protein, albumin, globulin, urea, uric acid, 25-hydroxycholecalciferol, phosphorus, and ionized and total calcium) were measured. Under ketamine-medetomidine-morphine anesthesia, cytology tape strips and full thickness shell biopsies were collected aseptically for microbiologic, histologic (including scoring of biopsy quality), and ultrastructural evaluations. The TSDSs were low and ranged from 4 to 22 (median = 9) out of a possible score of 54. There were no correlations between TSDS and any hematologic or biochemistry parameter. The histologic quality of shell biopsies was good, and normal shell structure, by both light and electron microscopy, is described. Small clefts and pitting lesions were noted in 8/19 sections. There was no evidence of erosion, ulceration, inflammation, or infectious agents, but algae and diatoms were observed. Six biopsies yielded aerobic isolates (Chryseobacterium indologenes, Aeromonas hydrophila, Ralstonia pickettii, and Morganella morganii), whereas 11 shell samples grew various clostridial anerobes. No fungal organisms were cultured. Although the etiology of the lesions described remains unknown, the use of a scoring system in conjunction with full thickness biopsies is suggested to help standardize investigations into chelonian shell disease in the future.

Tolerance doses of cutaneous and mucosal tissues in ring-necked parakeets (Psittacula krameri) for external beam megavoltage radiation.

Currently used dosages for external-beam megavoltage radiation therapy in birds have been extrapolated from mammalian patients and often appear to provide inadequate doses of radiation for effective tumor control. To determine the tolerance doses of cutaneous and mucosal tissues of normal birds in order to provide more effective radiation treatment for tumors that have been shown to be radiation responsive in other species, ingluvial mucosa and the skin over the ingluvies of 9 ring-necked parakeets (Psittacula krameri) were irradiated in 4-Gy fractions to a total dose of either 48, 60, or 72 Gy using an isocentric cobalt-60 teletherapy unit. Minimal radiation-induced epidermal changes were present in the high-dose group histologically. Neither dose-related acute nor chronic radiation effects could be detected in any group grossly in cutaneous or mucosal tissue over a 9-month period. Radiation doses of 72 Gy in 4-Gy fractions were well tolerated in the small number of ring-necked parakeets in this initial tolerance dose study.

Inferring synaptic inputs from spikes with a conductance-based neural encoding model.

Descriptive statistical models of neural responses generally aim to characterize the mapping from stimuli to spike responses while ignoring biophysical details of the encoding process. Here, we introduce an alternative approach, the conductance-based encoding model (CBEM), which describes a mapping from stimuli to excitatory and inhibitory synaptic conductances governing the dynamics of sub-threshold membrane potential. Remarkably, we show that the CBEM can be fit to extracellular spike train data and then used to predict excitatory and inhibitory synaptic currents. We validate these predictions with intracellular recordings from macaque retinal ganglion cells. Moreover, we offer a novel quasi-biophysical interpretation of the Poisson generalized linear model (GLM) as a special case of the CBEM in which excitation and inhibition are perfectly balanced. This work forges a new link between statistical and biophysical models of neural encoding and sheds new light on the biophysical variables that underlie spiking in the early visual pathway.

Discrete Stepping and Nonlinear Ramping Dynamics Underlie Spiking Responses of LIP Neurons during Decision-Making.

Neurons in LIP exhibit ramping trial-averaged responses during decision-making. Recent work sparked debate over whether single-trial LIP spike trains are better described by discrete "stepping" or continuous "ramping" dynamics. We extended latent dynamical spike train models and used Bayesian model comparison to address this controversy. First, we incorporated non-Poisson spiking into both models and found that more neurons were better described by stepping than ramping, even when conditioned on evidence or choice. Second, we extended the ramping model to include a non-zero baseline and compressive output nonlinearity. This model accounted for roughly as many neurons as the stepping model. However, latent dynamics inferred under this model exhibited high diffusion variance for many neurons, softening the distinction between continuous and discrete dynamics. Results generalized to additional datasets, demonstrating that substantial fractions of neurons are well described by either stepping or nonlinear ramping, which may be less categorically distinct than the original labels implied.

Detection of persistent Cytauxzoon felis infection by polymerase chain reaction in three asymptomatic domestic cats.

Repeated polymerase chain reaction (PCR) testing of 3 asymptomatic domestic cats were positive for Cytauxzoon felis DNA, suggesting persistent infection. Two cats initially presented with clinical signs consistent with acute cytauxzoonosis and, in both cases, signs of illness resolved after treatment. Parasitemia was detected in peripheral blood smears from these cats upon presentation with illness and, at subsequent follow-up appointments, in the absence of clinical illness. Polymerase chain reaction analysis was positive for C. felis from blood sampled at each time point. A third cat, a housemate of a cat fatally infected with C. felis, was preventatively treated for infection at the time of the housemate cat's death. This contact cat, having never shown signs of clinical illness consistent with cytauxzoonosis infection, had no detectable parasitemia but was positive for C. felis on repeated PCR testing. Detection of asymptomatically infected cats allows for the possibility of a yet unrecognized population of infected domestic cats that may have the capacity to serve as an additional reservoir host for C. felis, altering the currently accepted paradigm of C. felis transmission to domestic cats through bobcats as the reservoir host. In cases of very low parasitemia, more sensitive means of parasite detection, such as PCR testing, may be necessary to detect infected cats. Increased detection of asymptomatically infected cats will aid in understanding the epidemiology of C. felis infection and enhance the ability to prevent this highly fatal infectious disease of domestic cats.

Clinical presentation and pathology of sarcocystosis in psittaciform birds: 11 cases.

Sarcocystosis in psittaciform birds occurs in several different presentations, making ante-mortem diagnosis challenging without specific laboratory tests. This study followed the course of 11 birds diagnosed with sarcocystosis by serologic analysis and/or post-mortem examinations during a 10-month period in 2006-07. The disease presented in three different clinical forms: an acute pulmonary disease (three birds), muscular disease (five), and neurological disease (three). Early diagnosis of sarcocystosis was possible through the combined used of plasma protein electrophoresis and indirect fluorescent antibody serology in birds presented with the neurological and muscular forms of the disease. In three of these birds the plasma electrophoretic patterns revealed marked hypergammaglobulinemia. All of the birds that presented with the acute pulmonary form developed similar gross and microscopic lesions. Definitive diagnosis was ultimately made by microscopic observation of intravascular pulmonary schizonts containing merozoites. Schizonts were identified in the cerebellum and brainstem in two birds with the neurological form of disease. Those birds that initially presented with severe lethargy and weakness were considered to suffer from the muscular form of disease if they had extreme elevations of muscle enzyme activities (creatine phosphokinase, aspartate aminotransferase) and beta and gamma globulins concentrations, and were seropositive for antibodies to Sarcocystis falcatula. In this group the progression of the disease varied. Two birds recovered completely, and secondary aspergillosis was diagnosed in three birds. The histopathological lesions observed are discussed and interpreted in light of earlier findings from experimental infections in budgerigars, which provide insights into the natural course of sarcocystosis in psittaciform birds.

Comparison between coelioscopy and coeliotomy for liver biopsy in channel catfish.

OBJECTIVE: To evaluate endoscopic liver biopsy and compare that technique with a standard coeliotomy biopsy technique in fish. DESIGN: Randomized controlled clinical trial. ANIMALS: 30 channel catfish (Ictalurus punctatus). PROCEDURES: 10 fish were randomly assigned into control, coeliotomy, and coelioscopy groups. Anesthesia was performed with a recirculating anesthesia machine. Body weight, PCV, and total protein (TP) concentration in blood as well as plasma activities of aspartate aminotransferase, creatinine phosphokinase, lactate dehydrogenase, and sorbitol dehydrogenase were measured before and after surgery. Standard ventral coeliotomy or coelioscopy was performed, and the biopsy specimens were scored histologically. RESULTS: Coeliotomy and coelioscopy procedures were well tolerated without acute deaths. Blood TP concentration and PCV decreased after surgery in the coelioscopy group because of intracoelomic fluid administration to aid visualization. Minor changes in activities for hepatic and muscular enzyme activities were apparent, but were not significantly different between the coelioscopy and coeliotomy groups. Coelioscopy and coeliotomy yielded biopsy specimens of similar diagnostic quality. However, coelioscopy permitted a more extensive evaluation of the viscera, and all 10 surgical wounds healed completely, compared with severe wound dehiscence in 3 of 10 fish that underwent coeliotomy. CONCLUSIONS AND CLINICAL RELEVANCE: Both coelioscopy and coeliotomy were capable of yielding antemortem liver biopsy specimens of diagnostic quality in catfish. Coelioscopy permitted a more detailed examination of the coelomic viscera through a smaller surgical incision, was less traumatic, and resulted in decreased wound dehiscence.

Hematology of the Pascagoula map turtle (Graptemys gibbonsi) and the southeast Asian box turtle (Cuora amboinensis).

Turtle populations are decreasing dramatically due to habitat loss and collection for the food and pet market. This study sought to determine hematologic values in two species of turtles to help assess health status of captive and wild populations. Blood samples were collected from 12 individuals of the Pascagoula map turtle (Graptemys gibbonsi) and seven individuals of the southeast Asian box turtle (Cuora amboinensis) from the Savannah River Ecology Laboratory (South Carolina, USA). The hematologic data included hematocrit, total solids, erythrocyte count, leukocyte count, and differential and percentage leukocyte counts. Low hematocrit values and high basophil counts were found in both species. The basophil was the most abundant leukocyte in the Pascagoula map turtle (median = 0.80 x 10(9)/L), whereas in the Southeast Asian box turtle the most abundant leukocyte was the heterophil (median = 2.06 x 10(9)/L).