Influence of emotional states on inhibitory gating: animals models to clinical neurophysiology

Abstract

Integrating research efforts using a cross-domain approach could redefine traditional constructs used in behavioral and clinical neuroscience by demonstrating that behavior and mental processes arise not from functional isolation but from integration. Our research group has been examining the interface between cognitive and emotional processes by studying inhibitory gating. Inhibitory gating can be measured via changes in behavior or neural signal processing. Sensorimotor gating of the startle response is a well-used measure. To study how emotion and cognition interact during startle modulation in the animal model, we examined ultrasonic vocalization (USV) emissions during acoustic startle and prepulse inhibition. We found high rates of USV emission during the sensorimotor gating paradigm and revealed links between prepulse inhibition (PPI) and USV emission that could reflect emotional and cognitive influences. Measuring inhibitory gating as P50 event-related potential suppression has also revealed possible connections between emotional states and cognitive processes. We have examined the single unit responses during the traditional gating paradigm and found that acute and chronic stress can alter gating of neural signals in regions such as amygdala, striatum and medial prefrontal cortex. Our findings point to the need for more cross-domain research on how shifting states of emotion can impact basic mechanisms of information processing. Results could inform clinical work with the development of tools that depend upon cross-domain communication, and enable a better understanding and evaluation of psychological impairment.

Keywords: Cognition; Electrophysiology; Emotion; Inhibition; Rat; Startle.

Figure 1

Histograms of USV emission for the 3 different sessions that vary in terms of predictability. A) This session replicated previous work using a variable interval (VI) schedule of trial delivery. Trials came at a VI = 12.5 s and trials included loud tone (PA), PPI (loud tone preceded by soft tone) and PP (soft tone alone). The timing and trial types were unpredictable. USVs rise gradually and then are maintained consistently throughout the session. USVs were seen consistently across all three trial types. B) This session (FI) used a fixed interval (15 s) between each trial. PPI did not change even with high predictability of timing for the trials. USVs were not reduced and slightly increased across all trials. C) Fixed interval and blocked session included highest predictability with 15 s FI along with blocks of trial types. The order of presentation made significant difference. In this example the soft tone trials do not elicit calls since they are at the session start. When at the end, the same PP block does lead to USV calling, as a generalization to the aroused and aversive state the animals have experienced with the repetitive loud tones (modified from Ref. [41]).

Figure 2

An example of a local field potential recorded from a single wire yields waveforms for both tones in a pared-throwing block of trials. A P60 occurred as a positive going peak 60 milliseconds after the first tone (C_tone) at 0 seconds. Another P60 occurred at 60 milliseconds after the second tone (T_tone) at 0.5 sec. Gating of the second tone is apparent in the diminished amplitude of P60 when compared to P60 following the first tone (modified from Ref. [19]).

Figure 3

We examined inhibitory gating by recording from neurons in the amygdala. Four different types of single unit responses were found in this limbic brain region. A) Excitatory response-short duration gating (E-SD). This response is a very brief increase in activity following the initial, conditioning tone. The increase in activity related to the tone response is completely absent from the test tone 2. B) Excitatory response-long duration (E-LD). This response was a sustained increase in activity following the test stimulus. In some cases, the increase in activity was prolonged through the onset of the conditioning stimulus 500 ms later. C) An example of anticipatory gating. A select set of cells showed this gradual activity increase prior to the initial tone that was absent prior to the second tone in the pair. D) An example of inverse gating (Inh). Some neurons showed an inhibition following the test stimulus that was significantly reduced at the time of the conditioning stimulus (modified from Ref [81]). The tone related activations are not consistently seen throughout a gating session but arise in clusters interspersed with reduced or absence activity to the stimulus. We explored this periodicity by examining whether or not responses to the stimuli were influenced by active movement (see Ref [84]). In most cases, the tone responses were dampened when the animal was active and intentional movement could be an important factor leading to the reduction or absence of the tone-related activity in certain sets of trials (e.g., during locomotion or grooming).

Figure 3

We examined inhibitory gating by recording from neurons in the amygdala. Four different types of single unit responses were found in this limbic brain region. A) Excitatory response-short duration gating (E-SD). This response is a very brief increase in activity following the initial, conditioning tone. The increase in activity related to the tone response is completely absent from the test tone 2. B) Excitatory response-long duration (E-LD). This response was a sustained increase in activity following the test stimulus. In some cases, the increase in activity was prolonged through the onset of the conditioning stimulus 500 ms later. C) An example of anticipatory gating. A select set of cells showed this gradual activity increase prior to the initial tone that was absent prior to the second tone in the pair. D) An example of inverse gating (Inh). Some neurons showed an inhibition following the test stimulus that was significantly reduced at the time of the conditioning stimulus (modified from Ref [81]). The tone related activations are not consistently seen throughout a gating session but arise in clusters interspersed with reduced or absence activity to the stimulus. We explored this periodicity by examining whether or not responses to the stimuli were influenced by active movement (see Ref [84]). In most cases, the tone responses were dampened when the animal was active and intentional movement could be an important factor leading to the reduction or absence of the tone-related activity in certain sets of trials (e.g., during locomotion or grooming).

Figure 4

Waveforms are representative of medial prefrontal cortex local field potential responses recorded from the same microelectrode during inhibitory gating. T/C ratios indicate the proportional relationships for each auditory evoked potential component in response to the initial or conditioning tone (C; black trace) and the second or test tone (T; gray trace) in Before (A), After conditioning (B), and Extinction sessions (modified from Ref. [19]).

Figure 5

Forebrain areas are potentially involved in various types of gating depending on the region and type of inhibition. Forebrain regions involved in cognitive gating include the cortex for executive function and decision making, and the hippocampus for short-term and working memory. Motivation gating in the striatum influences reward seeking behavior. Emotional gating in the amygdala plays a role in emotion regulation. The thalamus is involved in sensory gating and relays this information to forebrain areas. Likewise, networks in the midbrain, hindbrain, and spinal cord rely on central nervous system sensory gating via inhibition at every level.