Two Behavioral Tasks Reveal Motor and Learning Deficits in the YAC72 Mouse Model of Hunington's Disease

C.Lawhorn^1*; D.M.Smith²; L.L.Brown^1,2

1. Dept Neuroscience, 2. Dept Neurology, Albert Einstein Col. of Medicine, Bronx, NY, USA

While Huntington's disease (HD) mouse models provide us with important tools for investigating potential therapeutics, thorough and replicable phenotypic characterization is necessary to fully understand the genetic disorder in mice, and its relevance to the human disease. We used mice with yeast artificial chromosomes, containing human genomic DNA with 72 CAG repeats (YAC72), as a model for studying the relationship between the neuropathology and behavioral symptoms of HD (Hodgson et al, 1999). To determine quantifiable behavioral deficits in this model we used a novel and challenging sensorimotor coordination task called the wire maneuver task, and an accelerating rotarod. At 7 months old, YAC72 mice (n=7) showed no difference on the wire maneuver task compared to age matched controls (n=13). As we have previously reported, 13 month old YAC72 mice showed a performance deficit on the wire maneuver task. This deficit was replicated in a second group of 13 month old mutants (n=12) compared to age matched controls (n=10) with a 50% decrease in performance (Controls: 50 10 seconds; YAC72: 25 8 seconds). In addition, we tested 13 month old YAC72 mice and controls on two rotarod tasks. On an accelerating rotarod, control mice showed an improvement in their performance on the rod over 3 days of training. However, 13 month old YAC72 mice did not show a significant improvement across 3 days. Interestingly, wire maneuver scores were positively correlated with day 1 performance on the accelerating rotarod irrespective of genotype (r=.75, p <.001). On a constant speed rotarod YAC72 mice did not differ from controls at 9, 18 and 36 RPM. This is the first study of YAC72 mutant mice to a show: (1) a replicable behavioral deficit on a challenging sensorimotor coordination task and (2) a motor skill learning deficit on the rotarod. Furthermore, these data suggest that more challenging behavioral tasks might be necessary to detect deficits in the YAC72 mouse model of HD. Supported by: SFN Travel Fellows (CL); PHS NS21356 (LLB)

A Complex Motor Coordination Task that is Difficult for Huntington's Disease Mutant Mice Activates Anterior Dorsolateral Striatum

C.Lawhorn^1*, D.M.Smith² , L.L.Brown^1,2

¹ Dept Neuroscience, ² Dept Neurology, Albert Einstein Col Med, Bronx, NY

The striatum is involved in complex movement sequences (e.g. Aldridge and Berridge,1998). Huntingtons disease (HD) patients suffer from selective cell loss to the striatum and show difficulties in motor coordination and sequencing. In a yeast artificial chromosome mouse model for HD (YAC72), we observed that mutant mice also show deficits in motor coordination and sequencing on the wire maneuver task (Lawhorn et al, 2003). For the task, mice maintain themselves on a suspended wire. Those that are most effective at this task use a combination of forelimbs, hindlimbs and tail. To identify the neuroanatomical regions that show greatest activity during the wire maneuver task we used [14C] labeled 2-deoxyglucose (2DG;0.5 mg/kg i.p.) to measure glucose metabolism, an indirect measure of neural activity. Wild-type littermates to YAC72 mice performed the wire maneuver task for 30 minutes. Before testing, each mouse was screened for adequate grip strength using an automated grip strength meter. All animals were videotaped for later scoring of complex sequencing. Each mouse showed the greatest increase in metabolism in the anterior dorsolateral striatum, an area associated with motor grooming sequences (Aldridge and Berridge,1998) and cell loss in animal models of HD (Hodgson et al, 1999). In addition, mice whose scores reflected more complex sequences of movement showed higher levels of metabolic activity in the anterior dorsolateral striatum. These data represent the first functional measure for the wire maneuver task and support the idea that a specific striatal region plays a critical role in movement sequencing. Pathology in this region in YAC72 HD mutants may be the basis for their poor performance on the wire maneuver task. Finally, this task may be especially useful for identifying anatomical and physiological pathology in the dorsolateral striatum of HD mutants.

Neural Correlates of Attachment Anxiety and Attachment Avoidance in Romantic Love: An FMRI Study

A.Aron^1*, H.E.Fisher³, D.Mashek¹, G.Strong¹, P.Shaver⁵, M.Mikulincer⁶, H.Li¹, L.L.Brown⁴

¹ Psychol, ² Radiology, SUNY Stony Brook, Stony Brook, NY, USA ³ Anthrop., Rutgers Univ., New Brunswick, NJ, USA ⁴ Neurol., Albert Einstein Col Med, Bronx, NY, USA ⁵ Psychol, Univ. of California, Davis, Davis, CA, USA ⁶ Psychol, Bar Ilan Univ., Ramar Gan, Israel

The attachment behavioral system plays a major role in social behavior of most mammalian species. Central attachment style dimensions as assessed by self-report in adult humans are (1) anxiety about reciprocation of closeness and (2) avoidance of closeness. These dimensions make primary contributions to behavioral variation across persons in relationships. This functional magnetic resonance imaging study is the first to identify neural correlates of these attachment dimensions. Fifteen intensely in love individuals alternately viewed a photograph of their beloved (attachment-relevant stimulus) and of a familiar, emotionally neutral individual. Between-subjects (random-effects; SPM99) analyses examined correlations (p<.01) of attachment dimensions with the beloved-image-minus-neutral-image contrast. Anxious attachment correlated with right ventral tegmental area/hypothalamus activity (r=.57), areas linked with reward and autonomic responses like perspiring. These findings are consistent with heightened anxiety and behaviors similar to addiction in anxious attachment. Avoidant attachment correlated negatively with activity in the rostral anterior cingulate (r=-.64), consistent with findings of reduced activation in this region when subjects feel threatened; and negatively with activity in orbitofrontal (r=-.61) and premotor cortex (r=-.74) regions, consistent with findings that these areas are involved in expectation of reward and motivation, respectively, supporting untested hypotheses that for avoidant individuals normal neural processing of cognitive and emotional responses to close others are inhibited and there is an absence of approach motivation.

The Striosomal Labyrinth of the Striatum in Mice and it's Relationship to the Organization and Density of Blood Vessels: More Evidence for a Lattice-like Functional Organization in the Striatum

L.L.Brown^1,2*, O.Breuer³, D.M.Smith¹, C.Lawhorn²

1 Dept Neurol., 2 Dept Neurosci., Albert Einstein Col Med, Bronx, NY, USA

3 Ben Gurion Univ. of the Negev, Beer Sheva, Israel

We have previously suggested that there is a close connection between the striosomal labyrinth, corticostriate axon terminal field projection patterns and vessel architecture in the striatum by looking at data from human MRI scans (Brown et al., 2002). To test the assumption that striosomes and corticostriate projection patterns are correlated with the basic distribution of blood vessels, we examined 30 um slices from the striatum of five FVB mice and stained for striosomes using a mu receptor antibody (MOR1). Three-dimensional images of striosomes and vessels were constructed using Photoshop and Imaris software. The matrix was defined as the background of the images of the striatum. From the images, the overall organization of the vessels and striosomes was observed and the relative areas of matrix and striosomes, vessels, and their colocalization was calculated. Results show a vascular pattern of lenticulostriate arteries that parallel the external capsule. In addition, the vessels penetrate the striatum in a grid-like pattern. Striosomes appear to be located along the vessels, in between the grid-lines. Furthermore, colocalization of vessels was greater in the striosomes than in the matrix (mean SD: 5.0 1.6% and 2.0 0.1%, respectively; p=.007). The results provide further evidence that the functional organization of the striatum is based on a grid or lattice-like structure. In addition, the proximity of the striosomes to vessels suggests a humoral signal related to their function. Support Contributed By: PHS NS21356 (LLB)

Early stage intense romantic love activates cortical-basal-ganglia

reward/motivation, emotion and attention systems: an fMRI study of a dynamic network that varies with relationship length, passion intensity and gender. 

H. Fisher¹, A. Aron², D. Mashek², G. Strong²,H. Li²,L.L. Brown³ 

¹Dept. Anthropology, Rutgers University; ²Dept. Psychology and Dept.Radiology, SUNY at Stony Brook; ³Dept. Neurology and Neuroscience, Albert Einstein College of Medicine. 

Early stage romantic love is an intense, positive motivation-emotion state,

a cross-culturally universal phenomenon, and possibly a developed form of a specific mammalian drive to pursue preferred mates. We studied 9 women and 8 men who were intensely "in love," using functional Magnetic Resonance Imaging (fMRI). Relationship length ranged from 1-17 months, with a median duration of 7 months. Subjects alternately viewed a photograph of a beloved and a photograph of a familiar, emotionally neutral individual, interspersed with a distraction task. Group activation occurred in the ventral tegmental area (R), caudate nucleus (R>L), a putamen/globus pallidus/subthalamic nucleus trajectory (R), and medial prefrontal and lateral parietal cortices (R and L). Activity in regions of the head and body of the caudate that are typically associated with reward, motivation and attention was positively correlated with intensity of passion, as recorded in a self-report questionnaire. Activity in the anterior insula (R) and anterior cingulate (R>L) increased with relationship length. Women showed activity in more brain regions than men. This positive affect-motivation state was dynamic: it became increasingly limbic and cortical as the relationship lengthened. Also, it’s pattern was distinct from that of sexual arousal. The results suggest that multiple neural systems are associated with early stage intense romantic passion; among them are dopamine-modulated basal ganglia loops through the thalamus and cortex that may underlie the reward and motivation components of romantic love.

Motor Deficits and Striosomal Volume in the YAC72 Mouse Model of Huntington's Disease 

C. Lawhorn¹*; D.M. Smith²; B.R. Leavitt³; L.L. Brown^1,2  

¹Dept Neuroscience*, Albert Einstein Col Med, Bronx, NY, USA, ²Dept Neuorolgy, Albert Einstein Col Med, Bronx, NY, USA. ³Cntr for Molecular Med and Therapeutics, Univ of British Columbia, Vancouver, BC, Canada  

Abstract: The striatum has distinct neurochemical and functional compartments called striosomes, which are embedded in an extrastriosomal matrix. In early-stage Huntington’s disease (HD), there is some evidence that cell loss is specific to striosomal compartments (Hedreen and Folstein, 1995). To investigate whether striosome pathology mediates some of the motor symptoms in HD we used a yeast artificial chromosome transgenic mouse model of HD that expresses full-length human huntingtin with 72 CAG repeats (YAC72). We ran 15-month old YAC72 mice (n=10) and age-matched controls (n=10) on assays for motor function. All subjects were blindly pre-screened for general health using the SHIRPA protocol. Compared to controls, mutants showed a 70% decrease in their ability to remain on a suspended wire (Controls: 14±3 sec.; Mutants: 4±2 sec. on the wire). Footprint analyses revealed a 16% increase in the width between paws during locomotion compared to controls (Controls: 18±0.7 mm; Mutants: 21±1.2 mm). We used 3D reconstructions of coronal brain sections to determine striosome volume. Overall striatal volume did not differ between YAC72 and controls. However, striosome volume was 29% less than controls in mutants throughout the striatum, especially in posterior regions (Controls: 14±1%; Mutants: 10±1% striosome volume relative to whole striatum). Most importantly, wire maneuver scores were positively correlated with striosomal volume, yielding correlation coefficients of .76 across groups and .90 for controls alone. These data are the first to show a striosomal volume loss in a mouse model for HD, and the first to demonstrate a correlative relationship between natural motor behaviors and any striosomal measure.

Support Contributed By: APA/MFP in Neuroscience (CL); PHS NS21356 (LLB)

Activation of basal ganglia circuits with a neutral visual stimulus

A.G. Bleicher¹; M. Lipton¹; A. Popper²; L.L. Brown^2*

¹Radiology, Montefiore Med Ctr, Bronx, NY, USA ²Neurology, Albert Einstein Col Med, Bronx, NY, USA

Clinical data support the use of visual cues to ameliorate the symptoms of Parkinson s disease in its early and middle stages, although the brain regions that mediate this effect are unknown. The flashing checkerboard is a novel, valence neutral stimulus that intensely activates visual areas. To determine whether the basal ganglia are activated passively by this stimulus, eight (5M/ 3F) right-handed (Edinburgh Inventory) neurologically normal subjects were imaged in a 3.0 Tesla Philips/SMIS spectrometer. A flashing checkerboard (@2 Hz) was presented separately to the left and right hemifields in a block design with 27 sec stimulus epochs followed by 10.8 rest periods for a total of two complete cycles for each hemifield. Subjects focused on a central cross to minimize eye movements; no motor response was elicited from the subjects. Individual and group statistical analysis was performed using FSL, the FMRIB software library. Signal timecourses from active regions were extracted using AFNI. In all subjects, the most statistically significant response was detected in primary visual cortex and the tail, body and medial head of the caudate nucleus. Stimuli activated visual cortex contralaterally and caudate bilaterally. In the group analysis, we found activation of basal ganglia circuits including cortical, caudate, putamen, globus pallidus and thalamic regions. Activity in non-visual cortex increased in medial prefrontal, insular, anterior and posterior cingulate, visual parietal BA39, frontal eyefields, and supplementary motor cortex. These data suggest that visual stimuli activate several basal ganglia loops, including the body and tail of the caudate, which receive higher-order visual inputs and remain dopamine-rich in early Parkinson's disease. Thus, visual stimuli may ameliorate the symptoms of Parkinson s disease through visual regions of the basal ganglia.Support Contributed By: Albert Einstein College of Medicine and PHS NS21356 (LLB)