Opposite effects of tetanic stimulation of the auditory thalamus or auditory cortex on the acoustic startle reflex in awake rats

The amygdala mediates both emotional learning and fear potentiation of startle. The lateral amygdala nucleus (LA) receives auditory inputs from both the auditory thalamus (medial geniculate nucleus; MGN) and auditory association cortex (AAC), and is critical for auditory fear conditioning. The central amygdala nucleus, which has intra-amygdaloid connections with LA, enhances startle magnitude via midbrain connections to the startle circuits. Tetanic stimulation of either MGN or AAC in vitro or in vivo can induce long-term potentiation in LA. In the present study, behavioural consequences of tetanization of these auditory afferents were investigated in awake rats. The acoustic startle reflex of rats was enhanced by tetanic stimulation of MGN, but suppressed by that of AAC. All the tetanization-induced changes of startle diminished within 24 h. Blockade of GABAB receptors in the LA area reversed the suppressive effect of tetanic stimulation of AAC on startle but did not change the enhancing effect of tetanic stimulation of MGN. Moreover, transient electrical stimulation of MGN enhanced the acoustic startle reflex when it lagged behind acoustic stimulation, but inhibited the acoustic startle reflex when it preceded acoustic stimulation. The results of the present study indicate that MGN and AAC afferents to LA play different roles in emotional modulation of startle, and AAC afferents are more influenced by inhibitory GABAB transmission in LA.     

Primary and secondary neural networks of auditory prepulse inhibition: a functional magnetic resonance imaging study of sensorimotor gating of the human acoustic startle response

Feedforward inhibition deficits have been consistently demonstrated in a range of neuropsychiatric conditions using prepulse inhibition (PPI) of the acoustic startle eye-blink reflex when assessing sensorimotor gating. While PPI can be recorded in acutely decerebrated rats, behavioural, pharmacological and psychophysiological studies suggest the involvement of a complex neural network extending from brainstem nuclei to higher order cortical areas. The current functional magnetic resonance imaging study investigated the neural network underlying PPI and its association with electromyographically (EMG) recorded PPI of the acoustic startle eye-blink reflex in 16 healthy volunteers. A sparse imaging design was employed to model signal changes in blood oxygenation level-dependent (BOLD) responses to acoustic startle probes that were preceded by a prepulse at 120 ms or 480 ms stimulus onset asynchrony or without prepulse. Sensorimotor gating was EMG confirmed for the 120-ms prepulse condition, while startle responses in the 480-ms prepulse condition did not differ from startle alone. Multiple regression analysis of BOLD contrasts identified activation in pons, thalamus, caudate nuclei, left angular gyrus and bilaterally in anterior cingulate, associated with EMG-recorded sensorimotor gating. Planned contrasts confirmed increased pons activation for startle alone vs 120-ms prepulse condition, while increased anterior superior frontal gyrus activation was confirmed for the reverse contrast. Our findings are consistent with a primary pontine circuitry of sensorimotor gating that interconnects with inferior parietal, superior temporal, frontal and prefrontal cortices via thalamus and striatum. PPI processes in the prefrontal, frontal and superior temporal cortex were functionally distinct from sensorimotor gating.     

Involvement of nucleus accumbens dopaminergic transmission in acoustic startle: observations concerning prepulse inhibition in rats with entorhinal cortex lesions

The relationship between the entorhinal cortex and prepulse inhibition (PPI) as well as the nucleus accumbens dopaminergic participation in acoustic startle were examined in rats. After the entorhinal cortex was damaged bilaterally using ibotenic acid, a microdialysis probe was placed in the nucleus accumbens for detection of dopamine before, during and after acoustic startle stimuli. In rats with bilateral entorhinal cortex lesions PPI was reduced, and extracellular dopamine in the nucleus accumbens was elevated with or without acoustic stimuli. The entorhinal cortex and the sensorimotor gating system thus may be related via dopaminergic connections in the nucleus accumbens, even though dopamine release did not coincide completely with acoustic startle stimuli.     

Lesions of the perirhinal cortex but not of the frontal, medial prefrontal, visual, or insular cortex block fear-potentiated startle using a visual conditioned stimulus.

The present study is part of an ongoing series of experiments aimed at delineation of the neural pathways that mediate fear-potentiated startle, a model of conditioned fear in which the acoustic startle reflex is enhanced when elicited in the presence of a light previously paired with shock. A number of cortical areas that might be involved in relaying information about the visual conditioned stimulus (the light) in fear-potentiated startle were investigated. One hundred thirty-five rats were given 10 light-shock pairings on each of 2 consecutive days, and 1-2 d later electrolytic or aspiration lesions in various cortical areas were performed. One week later, the magnitude of fear-potentiated startle was measured. Complete removal of the visual cortex, medial prefrontal cortex, insular cortex, or posterior perirhinal cortex had no significant effect on the magnitude of fear-potentiated startle. Lesions of the frontal cortex attenuated fear-potentiated startle by approximately 50%. However, lesions of the anterior perirhinal cortex completely eliminated fear-potentiated startle. The effective lesions included parts of the cortex both dorsal and ventral to the rhinal sulcus and extended from approximately 1.8 to 3.8 mm posterior to bregma. Lesions slightly more posterior (2.3-4.8 mm posterior to bregma) or lesions that included only the perirhinal cortex dorsal to the rhinal sulcus had no effect. The region of the perirhinal cortex in which lesions blocked fear-potentiated startle projects to the amygdala, and thus may be part of the pathway that relays the visual conditioned stimulus information to the amygdala, a structure that is also critical for fear-potentiated startle. In addition, the present findings are in agreement with numerous studies in primates suggesting that the perirhinal cortex may play a more general role in memory.     

Tactile, acoustic and vestibular systems sum to elicit the startle reflex

The startle reflex is elicited by intense tactile, acoustic or vestibular stimuli. Fast mechanoreceptors in each modality can respond to skin or head displacement. In each modality, stimulation of cranial nerves or primary sensory nuclei evokes startle-like responses. The most sensitive sites in rats are found in the ventral spinal trigeminal pathway, corresponding to inputs from the dorsal face. Cross-modal summation is stronger than intramodal temporal summation, suggesting that the convergence of acoustic, vestibular and tactile information is important for eliciting startle. This summation declines sharply if the cross-modal stimuli are not synchronous. Head impact stimuli activate trigeminal, acoustic and vestibular systems together, suggesting that the startle response protects the body from impact stimuli. In each primary sensory nucleus, large, second-order neurons project to pontine reticular formation giant neurons critical for the acoustic startle reflex. In vestibular nucleus sites, startle-like responses appear to be mediated mainly via the vestibulospinal tract, not the reticulospinal tract. Summation between vestibulospinal and reticulospinal pathways mediating startle is proposed to occur in the ventral spinal cord.     

NMDA and non-NMDA antagonists infused into the nucleus reticularis pontis caudalis depress the acoustic startle reflex

The neural pathway that mediates the acoustic startle reflex has been proposed; however, the pharmacology underlying this reflex is less well known. The present study examined the role of excitatory amino acid receptors at the level of the nucleus reticularis pontis caudalis, a brainstem nucleus obligatory for the whole body startle reflex and implicated as the locus where extrinsic systems such as the amygdala may act to modulate acoustic startle. Twenty-nine rats, chronically implanted with bilateral cannulae aimed at the nucleus reticularis pontis caudalis, were tested to assess the effects of γ-d-glutamylglycine (DGG),dl-2-amino-5-phosphonopentanoic acid (AP5), and 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) on the amplitude of the acoustic startle reflex. Local infusion of each of the 3 compounds significantly reduced startle amplitude by as much as 70–80%. AP5 and CNQX attenuated startle over a dose range which indicated that the reticularis pontis caudalis may be much more sensitive to these compounds than other nuclei along the primary startle pathway. These results suggest that, at the level of the nucleus reticularis pontis caudalis, an excitatory amino acid neurotransmitter may mediate acoustic startle, and that both NMDA and non-NMDA receptor subtypes may be important for the expression of the acoustic startle reflex.     

Lesions of the central nucleus of the amygdala, but not the paraventricular nucleus of the hypothalamus, block the excitatory effects of corticotropin-releasing factor on the acoustic startle reflex.

Intracerebroventricular (icv) infusion of corticotropin-releasing factor (CRF) was previously found to produce a long-lasting, dose-dependent (0.1-1.0 microgram) increase in the amplitude of the acoustic startle reflex. The present study sought to determine where in the CNS CRF acts to increase startle. Intracisternal infusion of CRF (0.1-1.0 microgram) increased startle with a time course and magnitude similar to that produced by icv CRF, unlike intrathecal infusion, which produced a small, more rapid enhancement of startle. While lesions of the paraventricular nucleus of the hypothalamus had no effect on icv CRF-enhanced startle, bilateral lesions of the central nucleus of the amygdala significantly attenuated the excitatory effect of icv CRF but had no effect on intrathecal CRF-enhanced startle. Even though lesions of the amygdala blocked icv CRF-enhanced startle, local infusion of CRF into the amygdala did not significantly elevate startle. The present data indicate that the amygdala is part of the neural circuitry required for icv CRF to elevate startle, but does not appear to be the primary receptor area where CRF acts. The involvement of the amygdala in icv CRF-enhanced startle is consistent with the hypothesis that both the amygdala and CRF are critically involved in fear and stress.     

Cholinergic input from the ventral nucleus of the trapezoid body to cochlear root neurons in rats

Brain stem pathways are essential for the modulation of the acoustic startle reflex by sounds; nevertheless, the neural circuits that convey fast auditory information to the primary acoustic startle circuit are still unclear. In the rat, cochlear root neurons (CRNs) comprise the first component of the primary acoustic startle circuit and are critical in the initiation and full expression of the acoustic startle reflex. To determine whether CRNs receive auditory descending inputs, we developed tract-tracing studies combined with immunohistochemistry, electron microscopy, morphometry, and confocal microscopy. Either FluoroGold or biotinylated dextran amine (BDA) injections in CRNs showed retrogradely labeled neurons in the ventral nucleus of the trapezoid body (VNTB). We verified the projection to CRNs by injecting BDA into the VNTB. Our results showed that neurons from VNTB project bilaterally and directly to CRNs, giving off numerous endings onto cell bodies and preferentially dendrites of CRNs. Electron microscopy analysis of labeled VNTB terminals demonstrated that they made multiple symmetric synapses and contained small round vesicles. Colocalization of the vesicular acetylcholine transporter and fluorescein dextran after injection in the VNTB indicated that these terminals use acetylcholine as neurotransmitter. We also revealed that the inferior colliculus, an important nucleus mediating the auditory prepulse inhibition, projects to VNTB neurons that innervate CRNs. Our data show a novel and short descending auditory pathway from the VNTB to the first nucleus of the primary acoustic startle circuit that might play an important role in the auditory prepulse inhibition of the startle reflex elicited by sounds.     

Regulation of Prepulse Inhibition by Ventral Pallidal Projections

The acoustic startle reflex is inhibited by the presentation of a weak auditory prestimulus 30–500 ms prior to the startling stimulus. Previous studies have demonstrated that prepulse inhibition (PPI) of acoustic startle is regulated by GABAergic activity in the ventral pallidum. Ventral pallidal efferents include major projections to the pedunculopontine tegmental nucleus (PPTg), subthalamic nucleus (STN), and mediodorsal thalamus (MD). We used lesion and intracerebral infusion techniques to determine the relevance of these projections to the ventral pallidal regulation of PPI. Consistent with previous results, PPTg lesions significantly reduced PPI in all startle sessions, while MD lesions significantly reduced PPI only under certain experimental conditions. STN lesions failed to alter PPI, but they did significantly disrupt amphetamine-induced locomotion, verifying the behavioral effectiveness of these lesions. Infusion of the GABA-A agonist muscimol into either the PPTg or the MD significantly reduced PPI. Ventral pallidal projections to the PPTg and to the MD thus appear to regulate PPI, possibly via a GABAergic mechanism. Pallidal projections to the STN may regulate other behavioral processes such as locomotor activity, but they do not appear to regulate sensorimotor gating of the acoustic startle reflex.     

Roles of the glutamate receptor epsilon2 and delta2 subunits in the potentiation and prepulse inhibition of the acoustic startle reflex

We examined the regulation of the acoustic startle response in mutant mice of the N-methyl-D-aspartate (NMDA)- and delta-subtypes of the glutamate receptor (GluR) channel, which play important roles in neural plasticity in the forebrain and the cerebellum, respectively. Heterozygous mutant mice with reduced GluRepsilon2 subunits of the NMDA receptor showed strongly enhanced startle responses to acoustic stimuli. On the other hand, heterozygous and homozygous mutation of the other NMDA receptor GluRepsilon subunits exerted no, or only small effects on acoustic startle responses. The threshold of the auditory brainstem response of the GluRepsilon2-mutant mice was comparable to that of the wild-type littermates. The primary circuit of the acoustic startle response is a relatively simple oligosynaptic pathway located in the lower brainstem, whilst the expression of GluRepsilon2 is restricted to the forebrain. We thus suggest that the NMDA receptor GluRepsilon2 subunit plays a role in the regulation of the startle reflex. Ablation of the cerebellar Purkinje cell-specific delta2 subunit of the GluR channel exerted little effect on the acoustic startle response but resulted in the enhancement of prepulse inhibition of the reflex. Because inhibition of the acoustic startle response by a weak prepulse is a measure of sensorimotor gating, the process by which an organism filters sensory information, these observations indicate the involvement of the cerebellum in the modulation of sensorimotor gating.     

Neurochemical modulation of sensory-motor reactivity: acoustic and tactile startle reflexes

The present review argues that the startle reflex is particularly well suited as a model system to analyze how drugs alter stimulus reactivity and reflex excitability. It then reviews all the literature to date on how drugs or lesions that are thought to alter neurochemical transmitter systems affect acoustic and/or tactile startle. Hypotheses are presented to account for how serotonin, dopamine, norepinephrine, acetylcholine, and opiates modulate startle. Effects on startle plasticity such as habituation, sensitization, and potentiation resulting from prior associative learning are also included.     

Regulation of emotional responses elicited by threat-related stimuli

The capacity to voluntarily regulate emotions is critical for mental health, especially when coping with aversive events. Several neuroimaging studies of emotion regulation found the amygdala to be a target for downregulation and prefrontal regions to be associated with downregulation. To characterize the role of prefrontal regions in bidirectional emotion regulation and to investigate regulatory influences on amygdala activity and peripheral physiological measures, a functional magnetic resonance imaging (fMRI) study with simultaneous recording of self-report, startle eyeblink, and skin conductance responses was carried out. Subjects viewed threat-related pictures and were asked to up- and downregulate their emotional responses using reappraisal strategies. While startle eyeblink responses (in successful regulators) and skin conductance responses were amplified during upregulation, but showed no consistent effect during downregulation, amygdala activity was increased and decreased according to the regulation instructions. Trial-by-trial ratings of regulation success correlated positively with activity in amygdala during upregulation and orbitofrontal cortex during downregulation. Downregulation was characterized by left-hemispheric activation peaks in anterior cingulate cortex, dorsolateral prefrontal cortex, and orbitofrontal cortex and upregulation was characterized by a pattern of prefrontal activation not restricted to the left hemisphere. Further analyses showed significant overlap of prefrontal activation across both regulation conditions, possibly reflecting cognitive processes underlying both up- and downregulation, but also showed distinct activations in each condition. The present study demonstrates that amygdala responses to threat-related stimuli can be controlled through the use of cognitive strategies depending on recruitment of prefrontal areas, thereby changing the subject's affective state.     

Physiological abnormalities in hereditary hyperekplexia.

Five patients from a kindred with hereditary hyperekplexia had physiological testing. The surface-recorded electromyographic pattern of audiogenic muscle jerks was identical to that of the normal acoustic startle reflex. Testing at graded stimulus intensities indicated an increase in the gain of the acoustic startle reflex. Nose-tap stimuli resulted in short-latency generalized electromyographic bursts that were similar to the R1 component of the blink reflex. Electrical stimulation of peripheral nerves elicited a pattern of generalized muscle jerks that was similar to that of the acoustic startle reflex. Somatosensory evoked potentials, brainstem auditory evoked potentials, and cortical auditory evoked potentials were normal. The primary physiological abnormality in hereditary hyperekplexia is widespread elevated gain of vestigial withdrawal reflexes in the brainstem and possibly the spinal cord, most likely resulting from increased excitability of reticular neurons.     

Projections from orbitofrontal cortex to anterior piriform cortex in the rat suggest a role in olfactory information processing

The orbitofrontal cortex (OFC) has been characterized as a higher-order, multimodal sensory cortex. Evidence from electrophysiological and behavioral studies in the rat has suggested that OFC plays a role in modulating olfactory guided behavior, and a significant projection to OFC arises from piriform cortex, the traditional primary olfactory cortex. To discern how OFC interacts with primary olfactory structures, the anterograde tracer Phaseolus vulgaris leucoagglutinin was injected into orbitofrontal cortical areas in adult male rats. Labeled fibers were found in the piriform cortex and olfactory bulb on the side ipsilateral to the injection. Notably, the projection to piriform cortex was predominantly from ventrolateral orbital cortex, and was not uniform; rostrally, the projection to the ventral portion of the anterior piriform cortex (APC) was substantial, while the dorsal APC was virtually free of labeled fibers. Labeled fibers were found in both the dorsal and ventral portions in more caudal regions of APC. Most labeled fibers were found in layer III, although a substantial number of fibers were observed in layers Ib and II. Labeled fibers in posterior piriform cortex also were seen after injection into orbitofrontal areas. Taken together with previous reports, these findings suggest that piriform cortex includes multiple subdivisions, which may perform separate, parallel functions in olfactory information processing. Further, these results suggest that the OFC, in addition to its putative role in encoding information about the significance of olfactory stimuli, may play a role in modulating odor response properties of neurons in piriform cortex.     

Differential effects of dopamine agonists on acoustically and electrically elicited startle response: Comparison to effects of strychnine

This study sought to determine where drugs that are known to alter sensorimotor reactivity measured with the acoustic startle reflex ultimately act within the acoustic startle pathway. To do this, startle was elicited either acoustically or electrically within various nuclei believed to comprise the acoustic startle pathway. Direct infusion of serotonin into the subarachnoid space of the lumbar spinal cord increased acoustic startle and startle elicited electrically through the ventral cochlear nucleus (VCN) to a comparable degree. Subconvulsant doses of strychnine increased startle elicited acoustically or electrically through either the VCN or the nucleus reticularis pontis caudalis (RPC), pointing to spinal locus of action of strychnine after systemic administration. In marked contrast, the dopamine agonists d-amphetamine and apomorphine consistently increased acoustic startle but actually depressed startle elicited electrically through the VCN or the RPC. These later results suggest that dopamine agonists increase sensorimotor reactivity measured with acoustic startle by acting on sensory rather than motor parts of the reflex arc.     

Differential effects of dopamine agonists on acoustically and electrically elicited startle responses: comparison to effects of strychnine

This study sought to determine where drugs that are known to alter sensorimotor reactivity measured with the acoustic startle reflex ultimately act within the acoustic startle pathway. To do this, startle was elicited either acoustically or electrically within various nuclei believed to comprise the acoustic startle pathway. Direct infusion of serotonin into the subarachnoid space of the lumbar spinal cord increased acoustic startle and startle elicited electrically through the ventral cochlear nucleus (VCN) to a comparable degree. Subconvulsant doses of strychnine increased startle elicited acoustically or electrically through either the VCN or the nucleus reticularis pontis caudalis (RPC), pointing to a spinal locus of action of strychnine after systemic administration. In marked contrast, the dopamine agonists d-amphetamine and apomorphine consistently increased acoustic startle but actually depressed startle elicited electrically through the VCN or the RPC. These later results suggest that dopamine agonists increase sensorimotor reactivity measured with acoustic startle by acting on sensory rather than motor parts of the reflex arc.     

Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update

Frontal-subcortical circuits form the principal network, which mediate motor activity and behavior in humans. Five parallel frontal-subcortical circuits link the specific areas of the frontal cortex to the striatum, basal ganglia and thalamus. These frontal-subcortical circuits originate from the supplementary motor area, frontal eye field, dorsolateral prefrontal region, lateral orbitofrontal region and anterior cingulate portion of the frontal cortex. The open afferent and efferent connections to the frontal-subcortical circuits mediate coordination between functionally similar areas of the brain. Specific chemoarchitecture and multiple neurotransmitter interactions modulate the functional activity of each circuit. Dorsolateral prefrontal circuit lesions cause executive dysfunction, orbitofrontal circuit lesions lead to personality changes characterized by disinhibition and anterior cingulate circuit lesions present with apathy. The neurobiological correlates of neuropsychiatric disorders including depression, obsessive-compulsive disorder, schizophrenia and substance abuse, imply involvement of frontal-subcortical circuits.     

Small orbitofrontal traumatic lesions detected by high resolution MRI in a patient with major behavioural changes

We report a case of a male patient who showed personality changes and marked social problems after a traumatic brain injury. Although suspected to have lesions in the orbitofrontal cortex because of the typical characteristics of his behavioural change, lesions were not apparent using conventional imaging techniques. However, investigation using high-resolution MRI revealed lesions in the orbitofrontal cortex. Our case suggests that standard MRI scanning techniques may have only limited power. Hence, we stress the important role played by qualitative assessments of emotion, personality, and social behaviour in evaluating sequelae of traumatic orbitofrontal injuries.     

Electrophysiology meets fMRI: Neural correlates of the startle reflex assessed by simultaneous EMG–fMRI data acquisition

The startle reflex provides a unique tool for the investigation of sensorimotor gating and information processing. Simultaneous EMG–fMRI acquisition (i.e., online stimulation and recording in the MR environment) allows for the quantitative assessment of the neuronal correlates of the startle reflex and its modulations on a single trial level. This serves as the backbone for a startle response informed fMRI analysis, which is fed by data acquired in the same brain at the same time. We here present the first MR study using a single trial approach with simultaneous acquired EMG and fMRI data on the human startle response in 15 healthy young men. It investigates the neural correlates for isolated air puff startle pulses (PA), prepulse–pulse inhibition (PPI), and prepulse facilitation (PPF). We identified a common core network engaged by all three conditions (PA, PPI, and PPF), consisting of bilateral primary and secondary somatosensory cortices, right insula, right thalamus, right temporal pole, middle cingulate cortex, and cerebellum. The cerebellar vermis exhibits distinct activation patterns between the startle modifications. It is differentially activated with the highest amplitude for PPF, a lower activation for PA, and lowest for PPI. The orbital frontal cortex exhibits a differential activation pattern, not for the type of startle response but for the amplitude modification. For pulse alone it is close to zero; for PPI it is activated. This is in contrast to PPF where it shows deactivation. In addition, the thalamus, the cerebellum, and the anterior cingulate cortex add to the modulation of the startle reflex. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

额前皮质内侧区和眶回损伤后恐惧情绪管理改变的初步分析

目的 探讨额前皮质内侧区和眶回局限性损伤后恐惧情绪控制的变化模式及其神经结构基础.方法 对7例额前皮质内侧区和眶回损伤的病例进行MRI影像和心理测评比对分析,并进行统计描述.对照组为5例MRI影像正常的轻度颅脑创伤患者.结果 所有7例额前皮质内侧区和眶回损伤后患者均表现有情绪控制力下降,明显的反社会人格,对死亡的恐惧几近下降,攻击性显著增强,尤以2例眶回局限性损伤的患者表现突出.对照组中所有病例的情感等高级认知功能均正常,无反社会人格表现,恐惧管理表现正常,图片知觉整合能力正常,自我控制能力正常,无恐惧情绪控制异常.结论 额前皮质内侧区和眶回负责恐惧信息的评价,该部位损伤后可导致异常的主观情感状态和社会行为,因而额前皮质内侧区和眶回可能与恐惧信息的评价有关.