Biomedical subjects

John H Freeman

Publications and source records attributed to John H Freeman.

At least 19 recordsLinked to original sources

PubMed2006

Perirhinal cortex lesions impair feature-negative discrimination.

The role of the perirhinal cortex in inhibitory eyeblink conditioning was examined. In Experiment 1, rats were given lesions of the perirhinal cortex or control surgery and subsequently trained with a feature-negative discrimination procedure followed by summation and retardation tests for conditioned inhibition. Perirhinal cortex lesions impaired, but did not prevent acquisition of feature-negative discrimination. Results from the summation test showed that rats with perirhinal cortex lesions could not generalize feature-negative discrimination to a new stimulus. There were no group differences during the retardation test. Experiment 2 showed that lesions of the perirhinal cortex did not impair simple excitatory conditioning. Experiment 3 showed that perirhinal cortex lesions had no effect on acquisition of a simple tone-light discrimination. The results suggest that the perirhinal cortex plays a role in eyeblink conditioning when using discrimination procedures involving overlapping stimuli.

Analysis of Variance↗

PubMed2006

Medial auditory thalamic nuclei are necessary for eyeblink conditioning.

The auditory conditioned stimulus (CS) pathway that is necessary for delay eyeblink conditioning was investigated with induced lesions of the medial auditory thalamus contralateral to the trained eye in rats. Rats were given unilateral lesions of the medial auditory thalamus or a control surgery followed by twenty 100-trial sessions of delay eyeblink conditioning with a tone CS and then five sessions of delay conditioning with a light CS. Rats that had complete lesions of the contralateral medial auditory thalamic nuclei, including the medial division of the medial geniculate, suprageniculate, and posterior intralaminar nucleus, showed a severe deficit in conditioning with the tone CS. Rats with complete lesions also showed no cross-modal facilitation (savings) when switched to the light CS. The medial auditory thalamic nuclei may modulate activity in a short-latency auditory CS pathway or serve as part of a longer latency auditory CS pathway that is necessary for eyeblink conditioning.

Acoustic Stimulation↗

PubMed2006

Perirhinal cortex lesions impair simultaneous but not serial feature-positive discrimination learning.

The role of the perirhinal cortex in discriminative eyeblink conditioning was examined by means of feature-positive discrimination procedures with simultaneous (A-/XA+) and serial (A-/X-->A+) stimulus compounds. Lesions of the perirhinal cortex severely impaired acquisition of simultaneous feature-positive discrimination but produced no impairment in serial feature-positive discrimination. The results suggest that the perirhinal cortex plays a role in discriminative eyeblink conditioning by resolving ambiguity in discriminations with overlapping stimulus elements.

Animals↗

PubMed2005

Differential effects of cerebellar inactivation on eyeblink conditioned excitation and inhibition.

The neural mechanisms underlying excitatory and inhibitory eyeblink conditioning were compared using muscimol inactivation of the cerebellum. In experiment 1, rats were given saline or muscimol infusions into the anterior interpositus nucleus ipsilateral to the conditioned eye before each of four daily excitatory conditioning sessions. Postinfusion testing continued for four more excitatory conditioning sessions. All rats were given a final test session after muscimol infusions. The muscimol infusions inactivated the cerebellar nuclei, lateral anterior lobe, crus I, rostral crus II, and lobule HVI ipsilateral to the conditioned eye. Acquisition of excitatory conditioning was completely prevented by muscimol inactivation. In experiment 2, there were four experimental phases. Phase 1 consisted of excitatory conditioning. In phase 2, rats were given saline or muscimol infusions before conditioned inhibition training. Phase 3 consisted of continued conditioned inhibition training with no drug infusions. In phase 4, all rats received a retardation test in which the inhibitory stimulus was paired with the unconditioned stimulus. Muscimol infusions blocked the expression of conditioned responses during phase 2. However, robust conditioned inhibition was evident in phases 3 and 4. The findings indicate that conditioned excitation and inhibition depend on different mechanisms.

Animals↗

PubMed2005

Purkinje cell loss by OX7-saporin impairs excitatory and inhibitory eyeblink conditioning.

Cerebellar cortical contributions to eyeblink conditioned excitation have been examined extensively. In contrast, very little evidence exists concerning the role of the cerebellar cortex in eyeblink conditioned inhibition. In the current study, rats were given intraventricular infusions of the immunotoxin OX7-saporin to selectively destroy Purkinje cells throughout the cerebellar cortex following excitatory conditioning. After a 2-week postinfusion period, the rats were given reacquisition training. After reacquiring excitatory conditioning, the rats were trained in a feature-negative discrimination procedure to establish conditioned inhibition. Rats treated with OX7-saporin showed impaired reacquisition of excitatory conditioning and acquisition of conditioned inhibition. The results suggest that Purkinje cells play important, but different, roles in conditioned excitation and inhibition in rats.

Animals↗

PubMed2004

Impaired motor performance and learning in glia maturation factor-knockout mice.

Glia maturation factor (GMF) is a unique brain protein localized in astrocytes and some neuronal populations. Studies with overexpression of GMF using adenovirus vector have uncovered its regulatory role in intracellular signal transduction and downstream induction of biologically active molecules, including the neurotrophins and cytokines. The current paper deals with the behavior of mice devoid of GMF protein (knockout). GMF-null mice developed normally without gross abnormality. When tested for simple position discrimination using a T-maze and for spatial memory using a Morris water maze, the knockout mice performed as well as the wild-type, showing no defect in maze learning. However, with beam walking, GMF-knockout mice performed poorly and failed to learn. Knockout mice were also defective in learning the eyeblink classical conditioning. Histologically, the knockout mice showed a loss of neurons in the inferior olive, which is a component of the circuitry of eyeblink conditioning, and is also essential for motor performance. The structural abnormality in GMF-null mice explained their impaired ability for both motor performance and motor learning.

Animals↗

PubMed2004

Developmental changes in eyeblink conditioning and simple spike activity in the cerebellar cortex.

The activity of neurons in the cerebellum exhibits learning-related changes during eyeblink conditioning in adult mammals. The induction and preservation of learning-related changes in cerebellar neuronal activity in developing rats may be affected by the level of maturity in cerebellar feedback to its brainstem afferents, including the inferior olive. Developmental changes in cerebellar plasticity were examined by recording the activity of Purkinje cells in eye regions of cerebellar cortical lobule HVI (lobulus simplex) in infant rats during eyeblink conditioning. The percentage and amplitude of eyeblink conditioned responses increased as a function of age. Analyses of Purkinje cell simple spike activity revealed developmental increases in the number of units that exhibited stimulus-evoked and learning-related changes in activity. Moreover, the magnitude of these changes exhibited a substantial age-related increase. The results support the view that the emergence of learning-specific cerebellar plasticity and the ontogeny of eyeblink conditioning are influenced by developmental changes in the synaptic interactions within brainstem-cerebellum circuits.

Animals↗

PubMed2004

Selective developmental increase in the climbing fiber input to the cerebellar interpositus nucleus in rats.

Previous studies have demonstrated that learning-related cerebellar plasticity and stimulus-elicited neuronal activity emerge ontogenetically in parallel with delay eyeblink conditioning in rats. The present study examined cerebellar interpositus field potentials and multiunit neuronal activity evoked by microstimulation of the inferior olive in Postnatal Day 17 and 24 rats. The slope and amplitude of the excitatory postsynaptic potential and the number of evoked multiunit spikes increased with age, whereas the inhibitory postsynaptic potential caused by Purkinje cell input remained stable. These results are consistent with the notion that the postsynaptic depolarization of cerebellar interpositus neurons caused by cerebellar afferents (e.g., the climbing fibers of the inferior olive) is a critical factor contributing to the ontogeny of delay eyeblink conditioning in rats.

Animals↗

PubMed2004

Developmental changes in the neural mechanisms of eyeblink conditioning.

Eyeblink conditioning has been used as a model system for examining the ontogeny of associative learning and its neural basis in rodents. Associative eyeblink conditioning emerges between postnatal days (P) 17 and 24 in rats. Neurophysiological studies in infant rats during eyeblink conditioning revealed developmental changes in the activity of cerebellar neurons that correspond to the ontogenetic emergence of eyeblink conditioning. The developmental changes in cerebellar neuronal activity suggest that the ontogeny of eyeblink conditioning is related to changes in learning mechanisms rather than motor performance mechanisms. Additional neurophysiological and neuroanatomical studies demonstrated that the developmental changes in neuronal activity in the cerebellum are due to developmental changes in interactions between the cerebellum and its inputs, the inferior olive and pontine nuclei. Developmental changes in cerebellar inputs and regulation of its inputs affect the induction of learning-related plasticity, thereby affecting the rate and magnitude of conditioning.

Animals↗

PubMed2003

Developmental changes in evoked Purkinje cell complex spike responses.

The development of synaptic interconnections between the cerebellum and inferior olive, the sole source of climbing fibers, could contribute to the ontogeny of certain forms of motor learning (e.g., eyeblink conditioning). Purkinje cell complex spikes are produced exclusively by climbing fibers and exhibit short- and long-latency activity in response to somatosensory stimulation. Previous studies have demonstrated that evoked short- and long-latency complex spikes generally occur on separate trials and that this response segregation is regulated by inhibitory feedback to the inferior olive. The present experiment tested the hypothesis that complex spikes evoked by periorbital stimulation are regulated by inhibitory feedback from the cerebellum and that this feedback develops between postnatal days (PND) 17 and 24. Recordings from individual Purkinje cell complex spikes in urethan-anesthetized rats indicated that the segregation of short- and long-latency evoked complex spike activity emerges between PND17 and PND24. In addition, infusion of picrotoxin, a GABAA-receptor antagonist, into the inferior olive abolished the response pattern segregation in PND24 rats, producing evoked complex spike response patterns similar to those characteristic of younger rats. These data support the view that cerebellar feedback to the inferior olive, which is exclusively inhibitory, undergoes substantial changes in the same developmental time window in which certain forms of motor learning emerge.

Action Potentials↗

PubMed2003

Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning.

The acid-sensing ion channel, ASIC1, contributes to synaptic plasticity in the hippocampus and to hippocampus-dependent spatial memory. To explore the role of ASIC1 in brain, we examined the distribution of ASIC1 protein. Surprisingly, although ASIC1 was present in the hippocampal circuit, it was much more abundant in several areas outside the hippocampus. ASIC1 was enriched in areas with strong excitatory synaptic input such as the glomerulus of the olfactory bulb, whisker barrel cortex, cingulate cortex, striatum, nucleus accumbens, amygdala, and cerebellar cortex. Because ASIC1 levels were particularly high in the amygdala, we focused further on this area. We found that extracellular acidosis elicited a greater current density in amygdala neurons than hippocampal neurons and that disrupting the ASIC1 gene eliminated H+-evoked currents in the amygdala. We also tested the effect of ASIC1 on amygdala-dependent behavior; ASIC1-null mice displayed deficits in cue and context fear conditioning, yet baseline fear on the elevated plus maze was intact. These studies suggest that ASIC1 is distributed to regions supporting high levels of synaptic plasticity and contributes to the neural mechanisms of fear conditioning.

Acid Sensing Ion Channels↗

PubMed2003

Ontogeny of eyeblink conditioned response timing in rats.

Eyeblink conditioned response (CR) timing was assessed in adult and infant rats. In Experiment 1, adult rats were trained with a 150-ms tone conditioned stimulus (CS) paired with a periorbital shock unconditioned stimulus (US; presented at 200- or 500-ms interstimulus intervals [ISIs]). The rats acquired CRs with 2 distinct peaks that occurred just before the US onset times. Experiments 2 and 3 examined developmental changes in CR timing in pups trained on Postnatal Days 24-26 or 32-34. Experiment 3 used a delay conditioning procedure in which the tone CS continued throughout the ISIs. Pups of both ages exhibited robust conditioning. However, there were age-related increases in the percentage of double-peaked CRs and in CR timing precision. Ontogenetic changes in eyeblink CR timing may be related to developmental changes in cerebellar cortical or hippocampal function.

Aging↗

PubMed2003

Long-term retention of the classically conditioned eyeblink response in rats.

Retention of the classically conditioned eyeblink response in rats was tested with a conditioned stimulus (CS)-alone extinction test and 2 sessions of reacquisition training. Retention of the eyeblink conditioned response (CR) during both tests was highest 24 hr and 1 month after initial acquisition. Three months after initial acquisition, responding during the CS-alone test was at baseline, but there was significant savings during reacquisition. By 6 months after initial acquisition, the memory for the eyeblink CR was not expressed in either test. The group differences in retention, despite initial acquisition of the eyeblink CR to equal levels, suggest that rat eyeblink conditioning may provide a useful behavioral model for studying the neural processes underlying memory retention and loss.

Animals↗

PubMed2003

Addition of inhibition in the olivocerebellar system and the ontogeny of a motor memory.

The developmental emergence of learning has traditionally been attributed to the maturation of single brain regions necessary for learning in adults, rather than to the maturation of synaptic interactions within neural systems. Acquisition and retention of a simple form of motor learning, classical conditioning of the eyeblink reflex, depends on the cerebellum and interconnected brainstem structures, including the inferior olive. Here, we combined unit recordings from Purkinje cells in eye regions of the cerebellar cortex and quantitative electron microscopy of the inferior olive to show that the developmental emergence of eyeblink conditioning in rats is associated with the maturation of inhibitory feedback from the cerebellum to the inferior olive. The results are consistent with previous work in adult animals and indicate that the maturation of cerebellar inhibition within the inferior olive may be a critical factor for the formation and retention of learning-specific cerebellar plasticity and eyeblink conditioning.

Action Potentials↗

PubMed2002

Synapse formation is associated with memory storage in the cerebellum.

The idea that memory is encoded by means of synaptic growth is not new. However, this idea has been difficult to demonstrate in the mammalian brain because of both the complexity of mammalian behavior and the neural circuitry by which it is supported. Here we examine how eyeblink classical conditioning affects synapse number within the cerebellum; the brain region essential for long-term retention of the conditioned response. Results showed eyeblink-conditioned rats to have significantly more synapses per neuron within the cerebellar interpositus nucleus than both explicitly unpaired and untrained controls. Further analysis showed that the increase was caused by the addition of excitatory rather than inhibitory synapses. Thus, development of the conditioned eyeblink response is associated with a strengthening of inputs from precerebellar nuclei rather than from cerebellar cortex. These results demonstrate that the modifications of specific neural pathways by means of synaptogenesis contributes to formation of a specific memory within the mammalian brain.

Analysis of Variance↗

PubMed2002

Limbic thalamic lesions, appetitively motivated discrimination learning, and training-induced neuronal activity in rabbits.

A substantial literature implicates the anterior and mediodorsal (limbic) thalamic nuclei and the reciprocally interconnected areas of cingulate cortex in learning, memory, and attentional processes. Previous studies have shown that limbic thalamic lesions severely impair discriminative avoidance learning and that they block development of training-induced neuronal activity in the cingulate cortex. The present study investigated the possibility that the limbic thalamus and cingulate cortex are involved in reward-based discriminative approach learning, wherein head-extension responses yielding oral contact with a drinking spout that was inserted into the conditioning chamber after a positive conditional stimulus (CS+) were reinforced with a water reward but responses to the spout after a negative conditional stimulus (CS-) were not reinforced. In this task, the rabbits learned primarily to omit their prepotent responses to the spout on CS- trials. Acquisition was severely impaired in rabbits given limbic thalamic lesions before training. As during avoidance learning, posterior cingulate cortical neurons of control rabbits developed learning-related neuronal responses to task-relevant stimuli, but this activity was severely attenuated in rabbits with lesions. These results support a general involvement of the cingulothalamic circuitry in instrumental approach and avoidance learning. The fact that learning consisted of response omission indicated that the cingulothalamic role is not limited to acquisition or production of active behavioral responses, such as locomotion. It is proposed that cingulothalamic neurons mediate associative attention, wherein enhanced neuronal responses to stimuli associated with reinforcement facilitate the selection and production of task-relevant responses.

Acoustic Stimulation↗

PubMed2002

The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory.

Many central neurons possess large acid-activated currents, yet their molecular identity is unknown. We found that eliminating the acid sensing ion channel (ASIC) abolished H(+)-gated currents in hippocampal neurons. Neuronal H(+)-gated currents and transient acidification are proposed to play a role in synaptic transmission. Investigating this possibility, we found ASIC in hippocampus, in synaptosomes, and in dendrites localized at synapses. Moreover, loss of ASIC impaired hippocampal long-term potentiation. ASIC null mice had reduced excitatory postsynaptic potentials and NMDA receptor activation during high-frequency stimulation. Consistent with these findings, null mice displayed defective spatial learning and eyeblink conditioning. These results identify ASIC as a key component of acid-activated currents and implicate these currents in processes underlying synaptic plasticity, learning, and memory.

Acid Sensing Ion Channels↗

PubMed2002

Medial dorsal thalamic lesions impair blocking and latent inhibition of the conditioned eyeblink response in rats.

The effects of lesions of the medial dorsal thalamic nucleus (MD) on blocking and latent inhibition (LI) of the rat eyeblink response were examined in the present study. Previous work has demonstrated that the cingulate cortex and related thalamic areas are involved in processing conditioning stimuli throughout training. The experiments in the present study tested the hypothesis that disruption of cingulothalamic stimulus processing produced by lesions of the MD would impair 2 types of associative learning that involve decremental changes in attention. In Experiment 1, MD lesions severely impaired blocking. In Experiment 2, MD lesions severely impaired LI. The results indicate that lesions of the MD impair incremental, decremental, or both types of changes in stimulus processing during learning.

Animals↗