Ludise Malkova

• Georgetown University

Objective Area tempestas, a functionally defined region in the anterior piriform cortex, was identified as a crucial ictogenic trigger zone in the rat brain in the 1980s. However, whether the primate piriform cortex can trigger seizures remains unknown. Here, in a nonhuman primate model, we aimed to localize a similar trigger zone in the piriform c...

Serotonin signaling plays critical roles in social and emotional behaviors. Likewise, decades of research demonstrate that the amygdala is a prime modulator of social behavior. Permanent excitotoxic lesions and transient amygdala inactivation consistently increase social behaviors in non-human primates. In rodents, acute systemic administration of...

The nucleus accumbens (NAc) is a central component of the brain circuitry that mediates motivated behavior, including reward processing. Since the rewarding properties of social stimuli have a vital role in guiding behavior (both in humans and nonhuman animals), the nucleus accumbens is likely to contribute to the brain circuitry controlling social...

Decades of studies robustly support a critical role for the hippocampus in spatial memory across a wide range of species. Hippocampal damage produces clear and consistent deficits in allocentric spatial memory that requires navigating through space in rodents, non‐human primates, and humans. By contrast, damage to the hippocampus spares performance...

The bed nucleus of the stria terminalis (BNST) has been implicated in a variety of social behaviors, including aggression, maternal care, mating behavior, and social interaction. Limited evidence from rodent studies suggests that activation of the BNST results in a decrease in social interaction between unfamiliar animals. The role of the BNST in s...

Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating in which a low-intensity prepulse immediately precedes a startling stimulus, resulting in...

Goal-directed behavior and habit are parallel and, at times, competing processes. The relative balance of flexible, goal-directed responding as compared to inflexible habitual responding is highly dependent on experience (e.g., training history in a task) and conditions under which the behavior was formed. Reinforcer devaluation tasks have been use...

Cholinergic neurotransmission within the hippocampus has long been suggested to play a pivotal role in memory processing, based partly on the assumption that the well-established amnestic effects of systemic cholinergic receptor blockade are mediated by the hippocampus. However, experimental evidence suggests that this may not be the case; a growin...

The deep and intermediate layers of the superior colliculus (DLSC) respond to visual, auditory, and tactile inputs and act as a multimodal sensory association area. In turn, activity in the DLSC can drive orienting and avoidance responses—such as saccades and head and body movements—across species, including in rats, cats, and non-human primates. A...

The Hamilton Search Task (HST) is a test of nonnavigational spatial memory that is dependent on the hippocampus. The parahippocampal cortex (PHC) is a major route for spatial information to reach the hippocampus, but the extent to which the PHC and hippocampus function independently of one another in the context of nonnavigational spatial memory is...

The amygdala is a key component of the neural circuits mediating the processing and response to emotionally salient stimuli. Amygdala lesions dysregulate social interactions, responses to fearful stimuli, and autonomic functions. In rodents, the basolateral and central nuclei of the amygdala have divergent roles in behavioral control. However, few...

Neuropsychological and neuroimaging studies have suggested the presence of a fast, subcortical route for the processing of emotionally-salient visual information in the primate brain. This putative pathway consists of the superior colliculus (SC), pulvinar and amygdala. While the presence of such a pathway has been confirmed in sub-primate species,...

Epilepsy is associated with a variety of neuropsychiatric comorbidities, including both anxiety and depression. Despite high occurrences of depression and anxiety seen in human epilepsy populations, little is known about the etiology of these comorbidities. Experimental models of epilepsy provide a platform to disentangle the contribution of acute...

The basal ganglia are an evolutionarily old group of structures, with gross organization conserved across species. Despite this conservation, there is evidence suggesting that anatomical organization of a key output nucleus of the basal ganglia, the substantia nigra pars reticulata (SNpr), diverges across species. Nevertheless, there are relatively...

Reward contingencies are dynamic: outcomes that were valued at one point may subsequently lose value. Action selection in the face of dynamic reward associations requires several cognitive processes: registering a change in value of the primary reinforcer, adjusting the value of secondary reinforcers to reflect the new value of the primary reinforc...

(A) Amount of food consumed (in grams) during selective satiation does not differ across session types. Table shows the amount of food consumed for each animal on each session type. For infusions performed before satiation, mixed effects analysis revealed no significant main effects of food type (F1,15=2.6, p=0.13) or treatment (F0.3,2.1=0.87, p=0....

The capacity to adjust actions based on new information is a vital cognitive function. An animal's ability to adapt behavioral responses according to changes in reward value can be measured using a reinforcer devaluation task, wherein the desirability of a given object is reduced by decreasing the value of the associated food reinforcement. Element...

Selective, fiber-sparing excitotoxic lesions are a state-of-the-art tool for determining the causal contributions of different brain areas to behavior. For nonhuman primates especially, it is advantageous to keep subjects with high-quality lesions alive and contributing to science for many years. However, this requires the ability to estimate lesio...

Rapid and reflexive responses to threats are present across phylogeny. The neural circuitry mediating reflexive defense reactions has been well-characterized in a variety of species, for example, in rodents and cats, the detection of and species-typical response to threats is mediated by a network of structures including the midbrain tectum (deep a...

The amygdala is an integrator of affective processing, and a key component of a network regulating social behavior. While decades of lesion studies in nonhuman primates have shown alterations in social interactions after amygdala damage, acute manipulations of the amygdala in primates have been underexplored. We recently reported (Wellman, Forcelli...

The present study tested whether relational memory processes, as measured by the transverse patterning problem, are late-developing in nonhuman primates as they are in humans. Eighteen macaques ranging from 3-36 months of age, were trained to solve a set of visual discriminations that formed the transverse patterning problem. Subjects were trained...

Both hypoactivity and hyperactivity in the amygdala are associated with perturbations in social behavior. While >60 years of experimental manipulations of the amygdala in animal models have shown that amygdala is critical for social behavior, many of these studies contradict one another. Moreover, several questions remain unaddressed. (1) What effe...

Brain circuitry underlying defensive behaviors includes forebrain modulatory sites, e.g., the amygdala and hypothalamus, and midbrain effector regions, such as the deep/intermediate layers of the superior colliculus (DLSC). When disinhibited, this network biases behavior towards reflexive defense reactions. While well characterized in rodent models...

The perirhinal cortex (PRc) is essential for visual recognition memory, as shown by electrophysiological recordings and lesion studies in a variety of species. However, relatively little is known about the functional contributions of perirhinal subregions. Here we used a systematic mapping approach to identify the critical subregions of PRc through...

Unlike adult damage, neonatal damage to the inferior prefrontal convexity (IC) in monkeys spares learning and performance on the delayed nonmatching-to-sample (DNMS) task ( Málková et al. 2000). We investigated whether this sparing was due to compensation by undamaged orbital frontal cortex (O), an area also critical for DNMS, by comparing combined...

Significance Although the hippocampus has a well-documented role for spatial navigation across species, its role for spatial memory in nonnavigational tasks is uncertain. Thus, when monkeys are tested in tasks that do not require navigation through space, spatial memory seems unaffected by hippocampal lesions. However, the interpretation of these r...

Reports an error in "Ventral pallidum mediates amygdala-evoked deficits in prepulse inhibition" by Patrick A. Forcelli, Elizabeth A. West, Alice T. Murnen and Ludise Malkova (Behavioral Neuroscience, 2012[Apr], Vol 126[2], 290-300). It was incorrectly stated in the introduction and discussion that Alsene et al. (2011) had found that blockade of adr...

GABAergic neurons of the substantia nigra pars reticulata (SNpr) and globus pallidus pars interna (GPi) constitute the output pathways of the basal ganglia. In monkeys, choreiform limb dyskinesias have been described after inhibition of the GPi, but not the SNpr. Given the anatomical and functional similarities between these structures, we hypothes...

The orbitofrontal cortex (OFC) is critical for behavioral adaptation in response to changes in reward value. Here we investigated, in rats, the role of OFC and, specifically, serotonergic neurotransmission within OFC in a reinforcer devaluation task (which measures behavioral flexibility). This task used two visual cues, each predicting one of two...

Developmental prolongation is thought to contribute to the remarkable brain enlargement observed in modern humans (Homo sapiens). However, the developmental trajectories of cerebral tissues have not been explored in chimpanzees (Pan troglodytes), even though they are our closest living relatives. To address this lack of information, the development...

Stimulation of the intermediate and deep layers of superior colliculus (DLSC) in rodents evokes both orienting/pursuit (approach) and avoidance/flight (defense) responses (Dean et al., 1989). These two classes of response are subserved by distinct output projections associated with lateral (approach) and medial (defense) DLSC (Comoli et al., 2012)....

Cervical dystonia (CD; spasmodic torticollis) can be evoked by inhibition of substantia nigra pars reticulata (SNpr) in the nonhuman primate (Burbaud et al., 1998; Dybdal et al., 2012). Suppression of GABAergic neurons that project from SNpr results in the disinhibition of the targets to which these neurons project. It therefore should be possible...

Basolateral amygdala (BLA) function is critical for flexible, goal-directed behavior, including performance on reinforcer devaluation tasks. Here we tested, in rats, the hypothesis that BLA is critical for conditioned reinforcer devaluation during the period when the primary reinforcer (food) is being devalued (by feeding it to satiety), but not th...

Prepulse inhibition (PPI) is an operational measure of sensorimotor gating. It is defined as a reduction in magnitude of a startle response when a startling stimulus is preceded by a weaker "prepulse." PPI has been found to be altered in patients with schizophrenia, autism spectrum disorders, and other neuropsychiatric illnesses. As such, the neura...

The orbitofrontal cortex (OFC) and its interactions with the basolateral amygdala (BLA) are critical for goal-directed behavior, especially for adapting to changes in reward value. Here we used a reinforcer devaluation paradigm to investigate the contribution of OFC to this behavior in four macaques. Subjects that had formed associations between ob...

Flexible goal-directed behavior has been studied across species using reinforcer devaluation tasks, in which subjects form associations between specific stimuli (cues) and specific reinforcer(s). The reinforcer is subsequently devalued by selective satiation or taste aversion. Following devaluation, subjects adjust their responding to the cues refl...

Socioemotional abnormalities, including decreased social interactions and increased self-directed activity, were reported when rhesus monkeys with neonatal ablations of either the medial temporal lobe (AH) or the inferior temporal cortex (TE) were paired with unoperated peers at two and six months of age, though these abnormalities were more severe...

Nootropic agents or cognitive enhancers are purported to improve mental functions such as cognition, memory, or attention. The aim of our study was to determine the effects of two possible cognitive enhancers, huperzine A and IDRA 21, in normal young adult monkeys performing a visual memory task of varying degrees of difficulty. Huperzine A is a re...

To examine early brain development, T1-weighted structural MRI scans of seven rhesus monkeys (Macaca mulatta) were obtained longitudinally between the ages of 1 week and 4 years at 12 age points. Total brain volume, calculated at each age point, increased significantly, by 56%, between 1 week and 4 years. The greatest increase of 22% occurred betwe...

Nonhuman primate studies, using selective amygdala lesions that spare cortical areas and fibers of passage, have helped to clarify the amygdala's specific contribution to social and emotional behavior. M. D. Bauman, J. E. Toscano, W. A. Mason, P. Lavenex, and D. G. Amaral (2006) reported that macaque monkeys (Macaca mulatta) with neonatal neurotoxi...

Earlier studies found that recognition memory for object-place associations was impaired in patients with relatively selective hippocampal damage (Vargha-Khadem et al., Science 1997; 277:376-380), but was unaffected after selective hippocampal lesions in monkeys (Malkova and Mishkin, J Neurosci 2003; 23:1956-1965). A potentially important methodolo...

Amygdala ablation disrupts reinforcer "devaluation" in monkeys (Malkova et al., 1997). Here, we tested the hypothesis that transient inactivation of amygdala by the GABA(A) agonist muscimol (MUS), specifically during the period of reward satiation, would have a similar effect. Six pigtail macaques were trained on a visual object discrimination task...

In earlier studies of one-trial spatial memory in monkeys (Parkinson et al., 1988; Angeli et al., 1993), severe and chronic memory impairment for both object-place association and place alone was found after ablation of the hippocampal formation. The results appeared to provide the first clear-cut evidence in the monkey of the essential role of the...

To minimize the variability in the extent of lesions made by injections of the excitotoxin ibotenic acid in rhesus monkeys, we developed and validated an MRI-based method to determine the efficacy of the injections soon after surgery. T2-weighted MR images were obtained 6-11 days after surgery from 17 brain hemispheres of monkeys that had received...

Recent excitotoxic lesion studies in monkeys have shown that the recognition memory deficits originally attributed to amygdalo-hippocampal damage were due in whole or in part to the accompanying damage to surrounding tissue, including fibers of passage. Here we show that the same conclusion does not apply to the visual recognition impairment produc...

Normal infant monkeys and infant monkeys with neonatal damage to either the medial temporal lobe or the inferior temporal visual area were assessed in dyadic social interactions at 2 and 6 months of age. Unlike the normal infant monkeys, which developed strong affiliative bonds and little or no behavioral disturbances, the lesioned monkeys (each of...

Normal infant monkeys and infant monkeys with neonatal damage to either the medial temporal lobe or the inferior temporal visual area were assessed in dyadic social interactions at 2 and 6 months of age. Unlike the normal infant monkeys, which developed strong affiliative bonds and little or no behavioral disturbances, the lesioned monkeys (each of...

The ability of rhesus monkeys to master the rule for delayed nonmatching-to-sample (DNMS) has a protracted ontogenetic development, reaching adult levels of proficiency around 4 to 5 years of age (Bachevalier, 1990). To test the possibility that this slow development could be due, at least in part, to immaturity of the prefrontal component of a tem...

This book integrates neuroscience research on neuroplasticity with clinical investigation of reorganization of function after brain injury, especially from the perspective of eventually translating the findings to rehabilitation. Historical foundation in neuroplasticity research are presented to provide a perspective for recent findings. Leading in...

All previous reports describing alterations in emotional reactivity after amygdala damage in monkeys were based on aspiration or radiofrequency lesions which likely disrupted fibres of passage coursing to and from adjacent ventral and medial temporal cortical areas. To determine whether this associated indirect damage was responsible for some or al...

The present study reviews the long-term effects of neonatal hippocampal damage in monkeys on the development of memory functions and socioemotional behavior. The results showed that neonatal damage to the hippocampal formation impairs specific memory processes, such as those subserving automatic (as opposed to effortful) recognition memory and rela...

Studies have shown that excitotoxic lesions of the amygdala attenuate reinforcer devaluation effects in monkeys and rats. Because the rhinal (i.e., entorhinal and perirhinal) cortex has prominent reciprocal connections with the amygdala and has been suggested to store knowledge about objects, it is possible that it too composes part of the critical...

Aspiration lesions of the amygdala were found previously to produce a severe impairment in visual discrimination learning for auditory secondary reinforcement in rhesus monkeys (Gaffan and Harrison, 1987). To determine whether excitotoxic amygdala lesions would also produce this effect, we trained four naive rhesus monkeys on the same task. The mon...

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Aspiration lesions of the amygdala plus subjacent cortex were found earlier to produce a severe impairment in cross-modal (tactual-to-visual) recognition (Murray and Mishkin, 1985). To determine whether more selective lesions would also produce this effect, we trained 8 naive cynomolgus monkeys on a tactual-visual version of delayed nonmatching-to-...

The present study was aimed at determining whether early hippocampal damage alters the development of normal social interactions. Results showed that, at 2 months of age, animals with neonatal hippocampal lesions presented minor disturbances in initiation of social interactions. These subtle changes in behavior were less evident at 6 months, althou...

Rhesus monkeys with neonatal damage to either the medial temporal lobe or the inferior temporal cortical area TE, and their normal controls, were reassessed in visual habit formation (24-hour intertrial interval task) and visual recognition (delayed nonmatching to sample; DNMS) at 4-5 years of age and then tested on tactile and spatial DNMS. Result...

Strictly simultaneous eyelid conditioning in human Ss on the one hand and forward (ISI: 0.45 s), backward (ISI: -0.45 s), and pseudoconditioning on the other hand were compared in two different experimental situations: one-session experiment (100 reinforcements, 20 isolated CS randomly interspersed), and ten-sessions experiment (20 reinforcements,...

A method for type analysis of learning curves, based on the statistical mixture decomposition, is described. Some critical points in current data-analytic techniques are discussed. The mathematical rationale of the new method is outlined in a brief sketch. The possibilities of the method are documented by two examples. In the first study, done on s...