DL Rats Research Articles

Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071.

RationaleIn addition to the disease-defining motor symptoms, patients with Parkinson’s disease (PD) exhibit gait dysfunction, postural instability, and a propensity for falls. These dopamine (DA) replacement-resistant symptoms in part have been attributed to loss of basal forebrain (BF) cholinergic neurons and, in interaction with striatal dopamine (DA) loss, to the resulting disruption of the attentional control of balance and complex movements. Rats with dual cholinergic-DA losses (“DL rats”) were previously demonstrated to model PD falls and associated impairments of gait and balance.ObjectivesWe previously found that the muscarinic M1-positive allosteric modulator (PAM) TAK-071 improved the attentional performance of rats with BF cholinergic losses. Here, we tested the hypotheses that TAK-071 reduces fall rates in DL rats.ResultsPrior to DL surgery, female rats were trained to traverse a rotating straight rod as well as a rod with two zigzag segments. DL rats were refamiliarized with such traversals post-surgery and tested over 7 days on increasingly demanding testing conditions. TAK-071 (0.1, 0.3 mg/kg, p.o.) was administered prior to daily test sessions over this 7-day period. As before, DL rats fell more frequently than sham-operated control rats. Treatment of DL rats with TAK-071 reduced falls from the rotating rod and the rotating zigzag rod, specifically when the angled part of the zigzag segment, upon entering, was at a steep, near vertical angle.ConclusionsTAK-071 may benefit complex movement control, specifically in situations which disrupt the patterning of forward movement and require the interplay between cognitive and motor functions to modify movement based on information about the state of dynamic surfaces, balance, and gait.

Complex Movement Control in a Rat Model of Parkinsonian Falls: Bidirectional Control by Striatal Cholinergic Interneurons.

Older persons and, more severely, persons with Parkinson's disease (PD) exhibit gait dysfunction, postural instability and a propensity for falls. These dopamine (DA) replacement-resistant symptoms are associated with losses of basal forebrain and striatal cholinergic neurons, suggesting that falls reflect disruption of the corticostriatal transfer of movement-related cues and their striatal integration with movement sequencing. To advance a rodent model of the complex movement deficits of Parkinsonian fallers, here we first demonstrated that male and female rats with dual cortical cholinergic and striatal DA losses (DL rats) exhibit cued turning deficits, modeling the turning deficits seen in these patients. As striatal cholinergic interneurons (ChIs) are positioned to integrate movement cues with gait, and as ChI loss has been associated with falls in PD, we next used this task, as well as a previously established task used to reveal heightened fall rates in DL rats, to broadly test the role of ChIs. Chemogenetic inhibition of ChIs in otherwise intact male and female rats caused cued turning deficits and elevated fall rates. Spontaneous turning was unaffected. Furthermore, chemogenetic stimulation of ChIs in DL rats reduced fall rates and restored cued turning performance. Stimulation of ChIs was relatively more effective in rats with viral transfection spaces situated lateral to the DA depletion areas in the dorsomedial striatum. These results indicate that striatal ChIs are essential for the control of complex movements, and they suggest a therapeutic potential of stimulation of ChIs to restore gait and balance, and to prevent falls in PD.SIGNIFICANCE STATEMENT In persons with Parkinson's disease, gait dysfunction and the associated risk for falls do not benefit from dopamine replacement therapy and often result in long-term hospitalization and nursing home placement. Here, we first validated a new task to demonstrate impairments in cued turning behavior in rodents modeling the cholinergic-dopaminergic losses observed in Parkinsonian fallers. We then demonstrated the essential role of striatal cholinergic interneurons for turning behavior as well as for traversing dynamic surfaces and avoiding falls. Stimulation of these interneurons in the rat model rescued turning performance and reduced fall rates. Our findings indicate the feasibility of investigating the neuronal circuitry underling complex movement control in rodents, and that striatal cholinergic interneurons are an essential node of such circuitry.

Co-treatment with rivastigmine and idalopirdine reduces the propensity for falls in a rat model of falls in Parkinson's disease.

Falls in patients with Parkinson's disease (PD) are associated with cognitive, specifically attentional impairments and with losses in cholinergic projection systems. We previously established an animal model of the combined basal forebrain cholinergic-striatal dopaminergic losses of PD fallers (Dual Lesioned,DL, rats) and demonstrated that treating DL rats with an acetylcholinesterase inhibitor (AChEI), donepezil, together with a 5HT6 receptor antagonist, idalopirdine, reduced fall frequency and improved associated aspects of the performance ofDL rats traversing rotating rods. Here, we employed a longer and more taxing rotating beam apparatus to determine the potential therapeutic efficacy of idalopirdine when combined with the pseudo-irreversible, and thus relatively long-acting, AChE- and butyrylcholinesterase- (BuChE) inhibitor rivastigmine. As before, vehicle-treated DL rats fell more frequently, committed more slips, and exhibited more movement stoppages than intact control rats. Repeated intermittent administration of rivastigmine and idalopirdine significantly improved the performance of DL rats. Rivastigmine alone also produced strong trends for reducing falls and slips. The combination treatment was more effective than rivastigmine alone in reducing stoppages and stoppage-associated falls. As before, idalopirdine treatment alone was ineffective. These results extend the prediction that the combined treatment with idalopirdine and an AChEI improves complex movement control and reduces the propensity for falls in patients with movement disorders. Because of the importance of finding better treatments for gait and balance deficits in PD, the present results may further motivate a clinical exploration of the usefulness of this combination treatment.

Low-intensity pulsed ultrasound prevents muscle atrophy induced by type 1 diabetes in rats

BackgroundType 1 diabetes mellitus (T1DM) induces serious skeletal muscle atrophy. Low-intensity pulsed ultrasound (LIPUS) is a common treatment for skeletal muscle injury and is effective in accelerating the rate of muscle growth. However, to the best of our knowledge, whether LIPUS can improve skeletal muscle atrophy in type 1 diabetic rats has not been investigated.MethodsThe rats were randomly divided into four groups: the normal control group (NC); the sham-treated diabetic control group (DC); the diabetic, insulin-treated group (DI) as a positive control; and the diabetic LIPUS therapy group (DL). The DL rats were treated with LIPUS (1 MHz, 30 mW/cm2) on the gastrocnemius for 20 min/day.ResultsAfter 6 weeks, the rats in the DC group showed severe muscle atrophy. However, LIPUS significantly improved type 1 diabetes-induced muscle atrophy, as evidenced by significantly enhanced muscle cross-sectional area, muscle mass, and strength. Moreover, compared with the DC group, LIPUS significantly activated Akt and upregulated the expression of mTOR, and LIPUS downregulated the expression of MSTN, its receptor ActRIIB, and FoxO1.ConclusionsThese results indicate that LIPUS improved muscle atrophy induced by type 1 diabetes, and the MSTN/Akt/mTOR&FoxO1 signaling pathway may play a role in this improvement.

Effects of weight-bearing ladder and aerobic treadmill exercise on learning and memory ability of diabetic rats and its mechanism

To investigate the effects of climb ladder and aerobic treadmill exercise on learning memory ability in diabetic rats and explore its possible mechanisms. Forty male rats were randomly divided into normal control group (NC), diabetic control group (DC), diabetic loading ladder group (DL) and diabetic aerobic treadmill group (DA), diabetes was induced by a single intraperitoneal injection of STZ. In the evening, the DL group were trained three cycle (10 times/cycle) with weight-bearing climbing ladder, 2 min intervals, 6 days/week, lasted for six weeks. The DA group was trained on a motor-driven treadmill at a speed of 20 m/min (0 incline), 30 min/day, 6 days/week, lasted for six weeks. Morris water maze was used to detect the learning and memory ability of rats after modeling success and after exercise intervention. After the last water maze test, the rats were killed to obtain the hippocampus. RT-QPCR was used to detect the gene expressions of brain derived neurophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and cAMP-response element binding protein (CREB). Compared with NC group, the expressions of BDNF and CREB gene in hippocampus of DC group and the learning and memory ability were significantly decreased. Compared with DC group, the expression of BDNF and CREB in hippocampus of DL and DA rats was significantly up-regulated and the learning ability was significantly increased. The TrkB gene of hippocampus in DL rats was significantly up-regulated and the spatial memory ability was significantly improved. Compared with the DA group, the TRKB and CREB genes in the hippocampus of DL group were significantly up-regulated. Aerobic treadmill exercise and weight-bearing ladder exercise have a positive effect on the learning ability of diabetic rats, while the weight-bearing ladder exercise improves the memory ability of diabetic rats better than aerobic exercise. These effects may be related to the up-regulation of BDNF/TrkB/CREB signaling pathway.

The Effects of Lycopene and Insulin on Histological Changes and the Expression Level of Bcl-2 Family Genes in the Hippocampus of Streptozotocin-Induced Diabetic Rats

The aim of this study was to evaluate the effects of antioxidants lycopene and insulin on histological changes and expression of Bcl-2 family genes in the hippocampus of streptozotocin-induced type 1 diabetic rats. Forty-eight Wistar rats were divided into six groups of control (C), control treated with lycopene (CL), diabetic (D), diabetic treated with insulin (DI), diabetic treated with lycopene (DL), and diabetic treated with insulin and lycopene (DIL). Diabetes was induced by an injection of streptozotocin (60 mg/kg, IP), lycopene (4 mg/kg/day) was given to the lycopene treated groups as gavages, and insulin (Sc, 1-2 U/kg/day) was injected to the groups treated with insulin. The number of hippocampus neurons undergoing cell death in group D had significant differences with groups C and DIL (p < 0.001). Furthermore, insulin and lycopene alone or together reduced the expression of Bax, but increased Bcl-2 and Bcl-xL levels in DI, DL, and DIL rats, especially when compared to group D (p < 0.001). The ratios of Bax/Bcl-2 and Bax/Bcl-xL in DI, DL, and DIL rats were also reduced (p < 0.001). Our results indicate that treatment with insulin and/or lycopene contribute to the prevention of cell death by reducing the expression of proapoptotic genes and increasing the expression of antiapoptotic genes in the hippocampus.

Reducing falls in Parkinson's disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer's disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle-treated group, the combined treatment greatly reduced (Cohen's d=0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall-prone moments suggested that this treatment improved the efficacy and speed of re-instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait.

Long-lasting bradypnea induced by repeated social defeat.

Repeated social defeat in the rat induces long-lasting cardiovascular changes associated with anxiety. In this study, we investigated the effects of repeated social defeat on breathing. Respiratory rate was extracted from the respiratory sinus arrhythmia (RSA) peak frequency of the ECG in rats subjected to social defeat for 4 consecutive days. Respiratory rate was recorded under anesthesia 6 days (D+10) or 26 days (D+30) after social defeat. At D+10, defeated (D) rats spent less time in the open arms of the elevated plus maze test, had heavier adrenal glands, and displayed bradypnea, unlike nondefeated animals. At D+30, all signs of anxiety had disappeared. However, one-half of the rats still displayed bradypnea (DL rats, for low respiratory rate indicated by a lower RSA frequency), whereas those with higher respiratory rate (DH rats) had recovered. Acute blockade of the dorsomedial hypothalamus (DMH) or nucleus tractus solitarii (NTS) 5-HT3 receptors reversed bradypnea in all D rats at D+10 and in DL rats at D+30. Respiratory rate was also recorded in conscious animals implanted with radiotelemetric ECG probes. DH rats recovered between D+10 and D+18, whereas DL rats remained bradypneic until D+30. In conclusion, social stress induces sustained chronic bradypnea mediated by DMH neurons and NTS 5-HT3 receptors. These changes are associated with an anxiety-like state that persists until D+10, followed by recovery. However, bradypnea may persist in one-half of the population up until D+30, despite apparent recovery of the anxiety-like state.

Impact of short‐term aerobic and resistance training on acute post‐exercise blood glucose in Type 1 diabetic rodents

Despite the benefits of exercise (EX), physical activity levels are lower in Type 1 diabetics (T1D) due to the frequency of EX‐induced hypoglycemia. The objective of this study was to examine T1D post‐EX blood glucose (BG) levels in response to different EX modalities and to determine if short‐term training can modulate these responses. Forty rats were randomly divided into 4 groups; sedentary T1D (CD), T1D high intensity EX (DH), T1D low intensity EX (DL) and T1D resistance EX (DR). For 6 weeks, DH and DL rats ran on a treadmill at 27m/min and 15m/min, respectively, whereas DR climbed a vertical ladder while weighted. BG was measured for 2hrs post‐EX at week 3 and week 6. At week 3, DH had a significant fall in BG post‐EX, which sustained for 75min (p&lt;0.05). DH demonstrated similar immediate reductions in BG at week 6; however, BG returned to pre‐EX values by 45min (p&lt;0.05). DL had a significant drop in BG post‐ EX for &gt;2hrs (p&lt;0.05) at week 3; while at week 6, no immediate reductions in BG were evident up to 2hrs post‐EX. In contrast to aerobically trained animals, DR exhibited a post‐EX BG time course that was not significantly different from the BG regulation of CD animals throughout the 6 week study. To conclude, different EX modalities lead to differential regulation of BG following EX. In DH and DL, there appears to be a glucoregulatory adaptation to training that was not evident in DR rats. Supported by CIHR Grant #CCT‐ 83029.

The effect of losartan treatment on the response of diabetic cardiomyocytes to ATP depletion

The present work aimed to investigate the effect of losartan treatment of healthy and diabetic rats on cardiomyocyte response to ATP depletion. Cells were isolated from normoglycemic (N) and streptozotocin-injected (55 mg/kg) rats (D) treated or not treated with losartan (20 mg/kg/day in the drinking water; NL and DL, respectively) for 3 weeks. In each group of cells, enzyme activities such as glucose-6-phosphate (G6PDH) and glycerol-3-phosphate dehydrogenases (G3PDH), lactate/pyruvate, glycogen levels and citrate synthase were measured as an index of glycolytic dysregulation and mitochondrial mass, respectively. Cells were then challenged with NaCN (2 mM) in glucose-free Tyrode solution (metabolic intoxication, MI), a protocol to study ischemia at cell level. Under these conditions, the time to contractile failure up to rigor-type hyper-contracture in field-stimulated cells and K ATP current activation by patch-clamp recordings were measured. In comparison with N and NL, D cells presented higher G6PDH and cytoplasmic G3PDH activities, lactate/pyruvate, glycogen content but similar levels of citrate synthase, and decay time of contraction. When subjected to MI, D cells showed delayed activation of the K ATP current (25.7 ± 7.1 min; p < 0.001 vs. N and NL), increased time to contractile failure and rigor-type hyper-contracture ( p < 0.001 vs. N and NL). In cells from DL rats both functional (time to rigor and to K ATP current activation) and metabolic parameters, approached values similar to those measured in N and NL cells. These results demonstrate that diabetic cardiomyocytes from rats treated with losartan, maintain the capacity to respond promptly to ATP depletion reaching contractile failure, rigor-type hypercontracture and K ATP opening with a similar timing of N cells.

Baclofen, raclopride, and naltrexone differentially affect intake of fat/sucrose mixtures under limited access conditions

This study assessed the effects of the opioid antagonist naltrexone, the dopamine 2-like (D2) antagonist raclopride, and the GABA B agonist baclofen on consumption of fat/sucrose mixtures (FSM) using a limited access protocol. Sixty male Sprague-Dawley rats were grouped according to two schedules of access (Daily [D] or Intermittent [I]) to an optional FSM. Each FSM was created by whipping 3.2% (L), 10% (M), or 32% (H) powdered sugar into 100% vegetable shortening in a w/w manner ( n = 10 per group). One-hour intakes of the IL and IM groups were significantly greater than intakes of the respective DL and DM groups, thus fulfilling our operational definition of binge-type eating in these groups. Baclofen reduced intakes of the L and M mixtures regardless of access schedule, but failed to reduce intake of the H mixture. Naltrexone reduced intake in all groups, but potency was greater in IL rats than in DL rats. Furthermore, potency was attenuated in Intermittent rats, but enhanced in Daily rats, at higher sucrose concentrations. Raclopride reduced intake in the DL and stimulated intake in the IL groups, reduced intake in both M groups, and was without effect in both H groups. These results indicate that fat/sucrose mixtures containing relatively low concentrations of sucrose allow distinctions to be made between: 1) intakes stimulated by different access schedules and 2) opioid and dopaminergic modulation of those intakes. These results also suggest that brief bouts of food consumption involving fatty, sugar-rich foods may prove to be particularly resistant to pharmacological intervention.

Assessment of Mitochondrial DNA Polymorphisms in Salt-Sensitive Hypertension in Dahl Salt-Sensitive Rats

The Dahl salt-sensitive (DS) rat is the most prevalently used animal model of salt-sensitive hypertension. The purpose of the present study was to test the hypothesis that mitochondrial DNA (mtDNA) polymorphisms influence blood pressure in DS rats. We produced two strains of female F1 rats, one from female DS and male Lewis rats (DL) and the other from Lewis female and DS male rats (LD). These two strains had the same autosomal genetic background, but their mitochondria had different origins. The DL and LD rats had DS and Lewis mitochondria, respectively. A high-salt diet was started at 4 weeks of age. Radiotelemetry devices were implanted into the lower abdominal aorta of these F1 rats at 9 weeks of age. Blood pressure was monitored for 24 h at 11, 12, 13, 14, and 19 weeks of age. No significant differences were observed in blood pressure levels between the strains. Although more than 100 polymorphisms were detected between DS and Lewis rats, it is unlikely that polymorphisms in mtDNA contribute to hypertension in DS rats. Moreover, we found no difference between DS and Lewis rats in the mtDNA copy number in the kidneys, the liver, and the ventricles of the heart before and after salt loading. Thus, it is unlikely that mitochondrial dysfunction due to high blood pressure exacerbated target organ damage. Intriguingly, the time course of body weight gain differed significantly between DL and LD F1 rats, suggesting the influence of mitochondrial polymorphisms on body composition.

Partial leptin restoration increases hypothalamic-pituitary-adrenal activity while diminishing weight loss and hyperphagia in streptozotocin diabetic rats

Chronic leptin administration at pharmacologic doses normalizes food intake and body weight in streptozotocin (STZ)-diabetic rats. We examined the metabolic effects of acute partial physiological leptin restoration in STZ-diabetic rats by using subcutaneous osmotic mini pumps. Groups: (1) Rats infused with vehicle (DV); (2) rats infused with recombinant murine methionine leptin (DL) at 4.5 μg · (kg body weight · d)−1; (3)pair-fed rats (DP) given a food ration matching that consumed by the DL group. A fourth group of nondiabetic, normal (N) rats was also studied to assess normal metabolic efficiency, hypothalamic-pituitary-adrenal (HPA) activity and sympathoadrenal activity. Following leptin infusion, food consumption by DL rats was significantly lower than in DV rats. Paradoxically, despite a similar food intake to that of the DP group, which demonstrated a 40% reduction in body mass, DL rats increased their initial body weight by ∼20% (P < .05). Plasma corticosterone and ACTH concentrations were elevated by 2-fold to 3-fold in DL versus N, DP, and DV rats. In the pars distalis, glucocorticoid receptor (GR) mRNA levels were significantly higher in DL and DP rats compared with N and DV rats. Our results suggest that partial restoration of physiologic leptin: (1) successfully reduces hyperphagia while allowing body weight gain in STZ-diabetic rats; (2) increases corticosterone levels in STZ-diabetic rats, which may in turn counteract the anorexic effects of diabetes; and (3) is associated with increased pituitary GR mRNA levels, despite elevated corticosterone levels, suggesting that leptin may interfere with the negative feedback regulation of the HPA axis.

The effects of serotonin depletion and raphe grafts on hippocampal electrophysiology and behavior

The involvement of the serotonergic system in spatial learning and a possible correlation between serotonergic modulation of hippocampal electrical activity and spatial learning were studied in rats. Control, partial septal-lesioned (SL), 5,7-dihydroxytryptamine (5,7-DHT)-injected (DHT), double-lesioned (5,7-DHT and SL; DL), and DL rats that were transplanted with embryonic raphe grafts into the hippocampus (RG) were tested in a spatial task in a water maze and in an active avoidance shuttle-box task. The responses of the dentate gyrus (DG) to perforant-path (PP) stimulation were examined in the same rats, under the following conditions: (1) priming stimulation of the PP (testing feedback inhibition), (2) priming stimulation of the commissural pathway (testing feedforward inhibition), (3) during repeated stimulation of the PP at 7 Hz (frequency potentiation), and (4) following tetanic stimulation [long-term potentiation (LTP)]. DL, but not DHT or SL, treatment severely impaired the performance of rats in both reference- and working-memory tasks in the water maze. This effect was not seen in the shuttle box. The ability of the DG to exhibit LTP, which was reduced in the DHT and SL rats, was apparently similar to controls in the DL group, DL, but not DHT or SL alone, resulted in a reduction of inhibition in the DG. Both the behavioral deficits and the reduction in hippocampal inhibition were ameliorated by intrahippocampal raphe grafts. These results indicate that the serotonergic innervation of the hippocampus plays a role in spatial learning when the septohippocampal neurotransmission systems are disrupted. Furthermore, these results suggest that restoration of modulation of hippocampal inhibition, by raphe grafts, underlies the behavioral recovery observed in these rats.

Central action of sodium chloride on whole body pressor responsiveness in the DOCA-treated rat

This study investigated the effect of chronic intracerebroventricular (IVT) infusion of a hypertonic NaCl (400 mmol/l) artificial cerebrospinal fluid (aCSF) on blood pressure and whole body pressor responsiveness, in control rats (CH) and in rats implanted with deoxycorticosterone acetate (DOCA; DH). An isotonic aCSF was infused into another group of control (Cl) and DOCA (Dl) rats. Indirect systolic blood pressure (SBP) was measured using a tail-cuff technique once a week prior to and during the infusion period. Following 2 weeks of infusion, SBP increased significantly only in the DH and CH groups. In urethane-anaesthetized rats, the pressor response to intravenous infusions of norepinephrine and angiotensin II (Ang II) increased significantly in DH rats. When compared with Cl and Dl rats, those from the CH group also exhibited an enhanced response to norepinephrine and Ang II. However, this increase was not as great as in the DH animal. These results show that whole body pressor responses to norepinephrine and Ang II, increase in rats receiving chronic IVT infusion of hypertonic NaCl. These responses coincide with moderate but significant increases in SBP. These data indicate that sodium chloride acts at a central site to increase norepinephrine and Ang II pressor responsiveness in mineralocorticoid hypertension.

Postnatal development of dopaminergic cells in the rat retina.

By means of a histofluorescence technique (FGS method), a post-natal ontogeny of dopaminergic neurons (DA-cells) in the retina was studied in rats which had been born and reared under diurnal lighting (LD), reversed lighting (DL), constant lighting (LL), or continuous dark conditions (DD). The time of first appearance of DA-cells was not altered by any of the above conditions; weakly fluorescent cell bodies were visible at about the 10th postnatal day. After the eyes were open the DA fluorescence of the cell body was gradually increased in intensity in all LD, DL, and LL rats, but not for DD rats. At the 16-17th day the processes of the cell first became visible, extending laterally to the inner plexiform layer. The somata and their processes appeared to be well developed at the postnatal 4-6th week, and they resembled those of the adult rat. On the other hand, the DA-cells in the DD rats showed a weak fluorescence in both the somata and their processes. When the DD rats were transferred and reared under LD conditions for 1-3 days, the DA fluorescence was increased. These results strongly suggest that the initiation of retinal DA synthesis is independent of environmental lighting condition, but an adequate light stimulus is required for continued normal development of DA-cells. Unlike in the rat, fluorescent cells in the guinea pig and chick retinas were observed to be fairly mature at birth or hatching. The developmental pattern of DA-cells in the three species examined coincides with the maturation of visual function.